| Designation | Main cellular expression | Properties/Function |
| T cells | ||
| CD1 | Thymocytes. Langerhans cells | |
| CD2 | Mature T cells | Sheep erythrocyte (E Rosette) receptor: LFA-3 ligand |
| CD3 | Pan T cell marker | Part of T cell receptor complex |
| CD4 | Helper/inducer T cells | MHC class II receptor: HIV receptor |
| CD5 | Mature T cells. B cell subset (B1) | |
| CD8 | Cytotoxic/suppressor T cells | MHC class I receptor |
| CD25 | Activated T cells | IL-2 alpha receptor - New class of Regulatory T cells. |
| CD28 | T cells | CD80 receptor: T cell activation |
| CD38 | Thymocytes Activated cells | |
| CD71 | Activated T cells. Thymocytes | Transferrin receptor |
| Designation | Main cellular expression | Properties/Function |
| B cells | ||
| CD21 | B cells | CR 2 (Complement receptor). Recognizes C3d, the main C3b breakdown product, believed to be a modulator. Also EBV receptor. |
| CD23 | B cells | Low affinity IgE receptor |
| CD40 | B cells | Ig isotype switching |
| Surface Immunoglobulin | B cells | Ig isotype switching Antigen receptor |
| Designation | Main cellular expression | Properties/Function |
| Monocytes | ||
| CD14 | Monocytes | Receptor for Lipopolysaccharide |
| NK cells | ||
| CD16 | NK, monocytes | Fc gamma receptor III. |
| CD56 | NK, some T cells | |
| Designation | Main cellular expression | Properties/Function |
| General | ||
| CD11a | Leukocytes | cell adhesion ICAM-I receptor |
| 11b | NK cells | CR3 – phagocytosis |
| 11c | NK cells | CR4 – intercellular adhesion |
| CD15 | Lewis X antigen | |
| CD18 | Leukocytes | beta2 integrin associated with CD11 antigens |
| CD34 | Progenitor cells | L selectin ligand |
| CD35 | Monocytes, B cells, rbc’s, PMN’s, epithelial cells | CR1 – for phagocytosis. Recognizes C3b and C4b. Involved in clearing of circulating immune complexes (rbc’s) |
| CD43 | All leukocytes | sialophorin |
| CD45 | All leukocytes | Tyrosine phosphatase. T cell activation. Variable isoforms. |
| CD58 | All leukocytes | LFA 3; CD2 ligand |
| CD80 | Activated B/T cells, monocytes | CD28 receptor |
| HLA Class I | All leukocytes | Antigen presentation |
| HLA Class II | B cells, Monocytes, activated T cells | Antigen presentation |
Yes, this table from Nelsons really is this rubbish.
CD stands for cluster designation or cluster of differentiation.
Cytokines are small proteins that act locally to produce inflammatory/immune effects. Chemokines are ones with chemotactic properties (poor name); interleukins are ones that act between white cells. They have overlapping effects and are often synergistic as well as self regulating - makes them complicated to work out. All work by interacting with their ligands (=receptors) on the surface of the target cell. Most receptors are made up of chains, and often one or more chains are common to other receptors. Hence a gene defect can affect multiple receptors.
| Cytokine | Action |
| IL1 | Pro-inflammatory esp ICAM |
| IL2 | TH1 T helper cell response - cell mediated esp macrophages |
| IL4 | TH2 T helper cell response - antibody class switching eg allergy |
| IL10 | TH2 T helper cell response - antibody class switching eg allergy (inhibitory). Key product of TR1 regulatory T cells |
| IL15/16/21 | Cell mediated immunity |
| IL28 | antiviral, like IFN alpha/beta, but acts on IL10 receptor |
| TNF alpha | |
| TNF beta | cell mediated immunity |
| IFN gamma | cell mediated immunity |
Area 1 is mainly to do with pyogenic bacteria, area 2 is mostly intracellular pathogens.
Non-antigen-specific immune mechanisms are the less sophisticated and more primitive branch of the immune system (eg polymorphonuclear and mononuclear phagocytes, complement system). The specific (or adaptive) immune system is better because it can respond to antigens in a self-boosting way, and then creates "memory", resulting in faster and better responses next time. Actually the two branches are far from independent: many specific immune mechanisms use the nonspecific elements as effectors, and the nonspecific system is often enhanced by factors produced by the specific immune response.
One of the most important humoral (ie circulating) defense systems, responsible for :
The key component in this system is C3b, the active product of cleavage of the C3 molecule. Bound to an antigen it is a powerful opsonin, interacting with C3b receptors on neutrophils and monocytes. The splitting of C3 is achieved by:
C3b binding to a microorganism becomes self-amplifying, since C3b itself forms a component of the enzyme responsible for C3 cleavage. This needs strict control, and there are a number of regulatory proteins involved.
The later complement components C5-C9 are used to produce a membrane-attack complex which can lyse cell membranes - particularly important for systemic neisserial infections.
As well as lysis and opsonization, the complement reactions generate a variety of pharmacologically and chemotactically active by-products, eg C3a and C5a, which use these receptors:
CR3 and CR4 are both members of a family of adhesion molecules, the leukocyte beta integrins. See section on adhesion molecules.
MBL (also known as mannan-binding protein) is one of the collectins. It has some structural homology with the C1q component of the first complement component. Mannose on the surface of microorganisms gets bound, which opsonizes the organism via the classical complement pathway (uses serine protease MASP =MBL associated protein to fix C4 and C2). This is therefore independent of C1 and antibody! So MBL is an important opsonin in the early stages of infection (before antibody production) and in young children (with immature ability to produce antibodies), esp staph, candida. 40% of people are deficient (hetero or homozygous), associated with longer duration of illness!
A family of receptors for non-self antigens.
Alpha- and beta-interferons are families of proteins produced by virally infected cells. They have the ability to:
Gamma-interferon, though having some antiviral effect, is structurally poorly related to alpha- and beta-interferons, and is primarily a cytokine. Chief function is concerned with modulating immune responses esp effector cells; used therapeutically in Chronic Granulomatous Disease.
Many bacteria require iron for growth, and decreasing its availability is one mechanism of defense used by the host. Lactoferrin, an avid iron-binding protein, present in human milk has the effect of reducing the growth of E. coli. Serum iron often falls during infections, which is handy.
This enzyme with antibacterial properties is found in neutrophil lysosomes and in body secretions including tears and saliva.
Include clotting factors, amyloid proteins and C-reactive protein (CRP). Their precise biological role is not well characterized. CRP has some immune modulating effects and can act as a nonspecific opsonin for bacterial phagocytosis.
Found on all cells of the immune system plus on vascular endothelium. Expression is tightly controlled during inflammatory responses by cytokines. The first group of adhesion molecules is the selectins. L selectin is found on neutrophils and monocytes and binds to vascular endothelium. E and P selectin expression on endothelial cells during inflammation binds to leukocytes, esp sialyl lewis x, resulting in margination. This short term response is followed by expression of stronger adhesion molecules ie beta2 integrins. They are responsible for adherence of neutrophils to endothelium leading to escape from the circulation. They also have a fundamental role in cell to cell interaction and effector cell functions such as cytotoxicity. The group comprises dimeric proteins with a common beta subunit and variable alpha chain. They include molecules with some C3 receptor activity. Their expression is greatly up-regulated by the pro-inflammatory cytokines such as TNF-alpha or IL-1beta.
Many other adhesion molecules are recognized as being important in allowing homing of recirculating cells to certain sites, for example the mucosal surfaces, and in cell to cell interactions.
Phagocytic cells include neutrophils and monocyte/macrophages. Phagocytosis of a bacterium by a neutrophil involves:
Neutrophil numbers and function are generally enhanced by products of the inflammatory response, including cytokines and complement fragments.
Monocytes and macrophages do the same but slower and less efficient. However, key role vs intracellular microorganisms eg Mycobacterium tuberculosis and Listeria monocytogenes. Such pathogens are either recognized via opsonization or microbial mannose is recognized directly by MBL. They are also capable of cytotoxicity against infected host cells and malignant cells. The activity of macrophages is greatly enhanced by exposure to cytokines from T lymphocytes esp gamma-interferon. Macrophages also produce cytokines which have effects on other aspects of immune/inflammatory responses, an example being tumor necrosis factor alpha (TNF-alpha).
Natural killer (NK) cells form part of the null (non-T, non-B cell) lymphoid population. They recognize and kill tumor cells and virus-infected cells without prior sensitization. The precise mechanism of recognition is not known. They have surface receptors for the Fc part of IgG and when armed with specific IgG against a target cell antigen can also kill by a process called antibody-dependent cellular cytotoxicity (ADCC).
ie antigen stimulation of T and B cells triggers specific effector immune mechanisms eg antibody production or generation of specific cytotoxic T cells. An important step in this process is the presentation of antigen to the T lymphocyte. This is done mainly by specialized macrophages called antigen presenting cells (APC) but also by B cells. These cells take up antigens, degrade them to small peptides and then express them on the cell surface sitting in a groove in an accompanying major histocompatibility complex (MHC) molecule where it can then interact with a complementary groove in the T Cell receptor. Some MHC polymorphisms are better than others which helps explain genetic variability in immune responsiveness.
Several other receptor ligand interactions between the APC and the T cell eg via adhesion molecule are also important.
There are two arms of the specific immune system - antibody mediated and cell mediated.
Immunoglobulins are produced by B lymphocytes (and their derivative cells, plasma cells) in response to particular antigens from a microbe or a vaccine. Sometimes, specific antibodies may be present in the serum without prior exposure to the relevant antigen (so called 'natural' antibodies, produced as a result of cross-reactivity between antigens, esp polysaccharide).
The variable region on an antibody gives it its unique specificity. This variability occurs because V, D and J regions are randomly put together to create 10exp12 possible combinations. All this DNA manipulation is the reason B cells can often become malignant.
There are five main classes of immunoglobulin, which vary with respect to their ability to neutralize, opsonize, activate complement, cross the placenta etc. The immunoglobulin class is determined by the type of heavy chain present (the main chain).
Antibodies are produced by B (bone marrow derived) cells. B cells initially mature independent of antibody, but once Ig is expressed on the surface, a process of selection will begin. Some of the Ig will be non-functional, others will be directed against self antigens and will need to be destroyed, the remainder will need to mature further. Much of this happens outside the marrow, with proliferation occurring out in lymph nodes (and tonsils, spleen etc), with somatic hypermutation causing more, minor changes in the Ig variable region. After positive selection, where B cells that interact nicely with T cells and dendritic cells (via CD40 ligand) are preserved, they then switch classes (the basic B cell will produce IgM only) and mature further into Plasma cells and Memory cells. The ability to switch class is preserved however, so that cells that end up in the gut can switch to IgA.
The full process requires the cooperation of antigen-specific T helper (CD4 +ve) cells and is regulated by T suppressor (CD8 +ve) cells. Isotype switching from IgM production to the other antibody classes is critically dependent on T/B cell interaction via the CD40 antigen on B cells and its ligand expressed on activated T cells. The responses to some antigens, eg bacterial polysaccharides, can result in limited antibody production without T cell help. There is no immunological memory generated in such responses.
The T (thymus-derived) cell system is responsible for the predominant immune responses to intracellular microbes and, in addition, has regulating effects via cytokines and growth factors on many other aspects of the immune response. T cells originate from bone marrow, but acquire their functional capabilities during maturation in the thymus. Here the cells undergo gene rearrangement to generate diversity in the variable domains of the T cell receptor. They also become educated with regard to self and nonself antigens. This education takes the form of both negative and positive selection. The former involves deletion of self-reactive clones, the latter selection of self reactive clones to develop a suppressor function against autoimmune reactions.
The T cell antigen receptor (TCR) has a similar arrangement of constant and variable parts. The majority (90%) of mature circulating T cells express alpha and beta chains and the minority gamma and delta chains.
During thymic maturation T cells also acquire important functional surface molecules. CD3 is expressed on all T cells and is closely associated with the TCR. Initially both CD4 and CD8 are expressed on the same cells, but by full maturation one or other molecule is expressed depending on the functional class of the cell. Most gammadelta T cells do not express CD4 or CD8. Their precise functional role is ill-understood.
The central cell in the immune response is the CD4 positive T helper cell . Once switched on by antigen presentation these cells develop in one of two ways -
Responses to an antigen may follow a TH1 or TH2 route depending on a complex set of circumstances. Once established these responses are self-amplifying in that production of interferon or IL-4 promotes TH1 and TH2 responses respectively and inhibits the other. There is much interest in learning more about these responses to allow therapeutic switching from TH2 to TH1 in allergic individuals. The functions of T cells can be summarized as:
Once T and B cells have engaged antigen via their specific receptors they must activate to generate the next step in the immune response. This activation may take the form of increased transcription of the genes for surface receptors such as CD40 ligand and the IL-2 receptor on T cells, IL-2 production and preparation for cell division. The conveyance of the 'message' from the membrane receptors to the nucleus is called signal transduction and several inherited molecular defects here result in failure of ce
Normal CD4:8 ratio is 2:1.
Fas ligand (CD 95) for apoptosis of mature T cells ie end of response. Possibly has role in autoimmune disease, transplant rejection. Also found in some tumour cells, vs cytotoxic T cells.
The central roles of the spleen are:
The spleen is important in the initial response to a pathogen, perhaps as a result of its role in IgM production, esp when encountering a polysaccharide antigen for the first time. Asplenic patients are unduly affected by encapsulated organisms that require antibody and complement for opsonization and clearance. In the absence of preformed antibody, the spleen is critical in clearing of the blood stream. This fact may explain why adults, who have developed an immunologic repertoire, and older children who have been given pneumococcal vaccine have a lower risk for overwhelming infection after splenectomy than asplenic children. Infants with congenital asplenia have profoundly impaired reticuloendothelial clearance mechanisms. Additionally, they have diminished T-lymphocyte responsiveness to a variety of antigens in comparison with age-matched controls.
Produced by staph, strep A/C&G, Yersinia. Normal MHC II binding of antigen presenting cells to T cells is very specific, involving all regions of the alpha and beta chain. Only 1 per million T cells will bind to a specific antigen in this way. But superantigen binds to 1 or more of the limited number of V-beta regions (variable regions on beta), so potentially activates 20-30% of all circulating T cells. Responsible for TSS, psoriasis and atopic dermatitis, EBV infectious mononucleosis, possibly acute rheumatic fever. Kawasaki’s is probably superantigen – but no single superantigen has been identified. Levin and Curtis propose that any superantigen can cause it, but it is an unusual (presumed genetic) response to exposure that leads to disease.
Clinical characteristics:
Test if:
If clinical suspicion of C1-INH deficiency, screening with serum C4 and C1-INH proteins is recommended.
It is recommended that patients chronically receiving blood products receive vaccination to hepatitis B.
Medications and drugs to avoid in patients with HAE:
If only mild manipulation, such as mild dental work, no prophylaxis is indicated if C1-INH replacement (C1INHRP) is immediately available (dose; see below). If C1INHRP is not available, then danazol or tranexamic acid (TA) prophylaxis is recommended as below. Injection of local anesthetic might precipitate an attack.
If considering more than mild manipulation, such as dental work, danazol is recommended (incl children; avoid in the first 2 trimesters of pregnancy). The recommended dosage is 10 mg/kg/day (maximum, 600 mg daily) for 5 days before and 2 days after the event. C1INHRP should be made immediately available when possible.
TA is thought not to be as predictable for acute prevention as danazol. The recommended TA dosage is 75 mg/kg/day (split 2 or 3 times per day) for 5 days before and 2 days after the event. C1INHRP is to be made immediately available when possible.
For intubation or major procedures:
If the patient experiences more than one severe event per month or is disabled more than 5 days per month, then consider prophylaxis with TA, androgens, or C1INHRP on demand. The number of events per year does not predict the severity of the next event or whether the first or next event will be an airway event.
The first-line therapy for treatment of a severe event is C1INHRP, with dosage and administration as above. If C1-INHRP is not available, other therapies might include increasing the danazol dose, TA, early use of adrenaline (might not be effective), pain management, intravenous fluids, or supportive care. Use of fresh frozen plasma (solvent detergent or regular) could theoretically worsen attacks and remains controversial.
| Treatment of acute HAE attack | Extremities, trunk | Face, neck | Abdominal attack | Laryngeal attack |
| Wait and see | + | ± | - | - |
| Tranexamic acid | + | + | + | + |
| C1-INH concentrate | - | ± | + | + |
| ICU | - | - | - | + |
General measures for treatment of acute attacks: (1) treat as early as possible before development of a full-blown attack (prodromal symptoms); (2) some patients receiving danazol can abort attacks by increasing the dose of danazol at the first signs or prodrome of an attack.
Dosages: (1) tranexamic acid (oral or intravenous), 25 mg/kg up to 1 g every 3 to 4 hours (maximum, 75 mg/kg/day); (2) C1-INH concentrate (intravenous), 500 units at less than 50 kg, 1000 units at 50 to 100 kg, and 1500 units at greater than 100 kg.
Consider intubation early in progressive laryngeal edema.
International Consensus Algorithm (Canada 2003), Journal of Allergy and Clinical Immunology Volume 114, Issue 3 , September 2004, Pages 629-637
The age of the child, the type of clinical problem (eg recurrent ENT/airway infections, or atypical infection) and the type of bugs found all contribute to the diagnosis. Under 1yr consider SCID (failure to thrive, chronic diarrhoea, recurrent viral infections, thrush) and DiGeorge. Antibody defects tend to present in later childhood; neutrophil problems in between.
| Total Lymph count (5th centile) | Age |
| 2.9 | 2-3/12 |
| 3.6 | 4-8/12 |
| 2.18 | 12-23/12 |
| 2.4 | 2-5yr |
| 2 | 7+yr |
| (Comans, JPed 1997;130:388) | |
On average, a young infant will get 5-6 resp infections per year; if day care + older sibs that goes up to 12/yr.
ESID diagnostic protocol is not particularly simple but does help by starting with clinical presentations. Clin Exp Immun 2006; 145:204
Age of Presentation:
Typical bugs:
Other clinical problems:
CD3 are T cells, which then subdivide into CD4 and CD8 T-helper cells. CD19 and 21 are B cells, CD56 are NK cells. CD4 numbers should exceed CD8 - reversed ratio seen in HIV. A specific NK problem has been described with increased susceptibility to herpesviruses and papillomaviruses. Abnormal NK numbers also seen in Chediak-Higashi, CD40 ligand and NEMO (?).
IgG Subsets are controversial - see below.
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.
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.
BCG causes lymphadenitis in CGD, but does not disseminate
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).
Chronic inflammatory problems occur (due to having intact upregulated phagocytic activity with reduced apoptosis):
Mums who are carriers of CGD can be symptomatic even with fairly decent percentages of functional neutrophils incl aspergillus! 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!
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.
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:
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
See also Abnormal white cells.
A lysosomal problem, so large vesicles seen in neutrophils which have reduced function. Associated with albinism, developmental delay, bleeding disorder. The connection is that all have granules, and the defect is in way that endoplasmic reticulum sorts different products into different granules.
Griscelli syndrome is similar, associated with albinism but not developmental delay or bleeding. Can predispose to haemophagocytic syndrome. Differentiate from Chediak Higashi by light microscopy of hair (unevenly distributed large melanin granules cf evenly distributed; white under polarized light cf polychromatic).
Hermansky Pudlak II has the albinism, developmental delay and bleeding, but has pigmented macrophages instead of funny neutrophils. The neutrophil numbers as well as function are reduced, whereas other subtypes do not have any immunodeficiency. Check bleeding time.
3 types, 1= beta2 integrin defect (no adhesion), 2=selectin ligand (a fucose transporter; no rolling), 3= RAP1. Classically delayed cord separation (but actually seen in any neutrophil disorder), skin ulcers esp perianal, periodontitis, raised white cell count (because they are stimulated but don't move about normally). Developmental delay and hepatosplenomegaly is seen in type 2, bleeding disorder seen in type 3.
Chemotaxis disorders tend to produce pretty mild disease eg periodontitis only...
Mixed bag of diseases, with combined T and B cell deficits. "Severe" tends to mean severe lymphopenia and panhypogammaglobulinaemia with poor prognosis. Usually a bone marrow problem, with defective maturation of precursors - so depending on where the block is there may or may not be T cells, B cells, NK cells. A problem further down the line at the signalling stage will tend to mean immunoglobulin is produced, but not functional, esp since T cell regulation is needed too. So the clinical picture may be of a combined defect even if B cells and immunoglobulin are present. On the other hand, some defects are "leaky", ie some precursors do manage to develop past the block by having reversion mutations causing somatic mosaicism. The other possible source of T cells if present is that they may be maternal (do FACS CD3 vs TCR to discriminate). To test, find appropriate T cell markers. Such T cells usually not functional but may ameliorate severity or prevent progression.
Affected babies appear well at birth and are normally grown. Problems usually start within the first few months of life. Common presentations are:
On examination (usually), no lymph nodes; no thymic shadow on chest X-ray (development of thymus requires appropriate signals from bone marrow). Hepatomegaly (?). Investigations usually reveal lymphopenia (<2.8 in first year), and there may or may not be NK cells - the exact pattern helps you work out where the block is. Odd results may reflect presence of maternal lymphocytes! Mitogen responses (proliferation studies) are usually absent. IgG will usually be present from Mum, but gets used up quickly! IgA and IgM may be present if B cells are present, but usually limited clonal diversity so not much function and no specific antibody responses.
B- NK- is ADA. B+ NK+ is IL7R defect. B+ NK- is gamma chain or JAK3 (the two bind to each other). B- NK+ is RAG or Artemis. Bare lymphocytes (T but not CD4) are HLA deficient.
Complex, because the defect can relate to cytokine signalling, T-cell receptor signalling, receptor gene recombination etc.
The biggest group are T- B+ NK-: the main cause is Gamma chain deficiency, which is X-linked. About 50% of all SCID. The Gamma chain is found in numerous cytokines (IL-2, 4, 7, 9 and 15), hence why it causes severe problems. JAK3 binds to gamma chain so causes an identical syndrome.
The next main group are T- B- NK-: Adenosine deaminase (ADA) deficiency is the main cause. Accumulation of toxic deoxyadenosine triphosphate (d-ATP) in lymphocytes leads to cell death. All cell lines are reduced. Additional features are:
Occasional cases of ADA deficiency have been described, where inexplicably, immune function is normal. The diagnosis is confirmed by assay of red cell ADA activity (Purine lab, Guy's). First trimester antenatal diagnosis is possible. Gene therapy is done in London and Paris.
Purine nucleoside phosphorylase (PNP) deficiency is initially less severe than ADA deficiency but progresses with age. It is autosomal recessive (gene is on chromosome 9). The toxic metabolite is deoxyguanosine triphosphate. Immunoglobulin levels and antibody responses are initially normal but in the late stages levels fall.
Reticular dysgenesis (autosomal recessive) is characterized by an absence of myeloid as well as lymphoid precursors, so no neutrophils or macrophages. Platelets and red cells are usually OK but can be low too! Even more severe than other forms of SCID, tends to present very early. Often GVHD rash. Hard to transplant...
The T- B- NK+ group are to do with VDJ recombination. The main one here is RAGs (recombination activating genes, 1 and 2) defect. If you can't recombine these variable areas, then you can't develop the necessary diversity in antigen receptors on T and B cells. Artemis and Ligase 4 similarly. NK don't use them so they're fine. Diagnose by looking at Ig gene rearrangements.
Ommen's syndrome is a leaky B- SCID, usually a RAG defect, but characterised by:
Diagnosis is confirmed by showing limited TCR Vbeta clonal populations (the few clones leaking past the block expand in the periphery to cause the signs. Differential is GVHD (usually milder, not lymph nodes usually), congenital ichthyosis and Nethertons syndrome. Interferon gamma may produce some clinical improvement but definitive treatment is with bone marrow transplantation.
The final group, T- B+ NK+, is a mixed bag of different problems, all to do with signal transduction:
Defects in cytokine production are not really SCID:
The following have normal cell populations but abnormal surface molecules:
Flow cubicle, sterile handling, Septrin, Itraconazole, IVIG prophylaxis. If unable to get flow, discharge from general paeds ward!
PEG-ADA available for ADA deficiency. Use d-ATP levels to guide dosing. Treat while looking for transplant match.
BMT or PBSC if match available. Haploidentical (ie parent) BMT have poor results in Europe but currently 80% success rates in UK (cf 97% success for full HLA match). No big breakthrough in BMT science, just incremental improvements in conditioning regimens, supportive care, graft manipulation. Non SCID success rate is currently 69%; the rate is actually falling as more risky cases are now taken on. MUD for Wiskot Aldrich has 85% 10yr survival rate; a good MUD, using genomic rather than serological matching, is probably just as good as a sibling transplant. Other issues:
Gene therapy: T cell count starts to rise from 12 weeks onwards. GVHD may present at that point, but resolves spontaneously. 8 patients done so far in UK, only 1 non-responder who was an adult (not surprising, too old for thymic reconstitution), 2 have stopped IVIG treatment. More done in Paris, but 2 cases of malignancy; risk associated with number of cells returned. New gene therapy trials for CGD and ADA-type SCID.
DNA repair happens in 2 different ways. In active replication stage, homologous repair uses sister chromatids as a template for repairing damaged area. Involves recognition factors and repair kinases. ATM (ataxia telangiectasia mutation) is instrumental here. BRCA1 is one of the repair kinases.
In resting phase, nonhomologous repair occurs eg VDJ recombination. RAG (recombination activation genes) 1&2 recognize break points. Then a variety of different factors open up sequences then join ends back together eg DNA ligase 4, Artemis, Cernunnos. Some defects lethal if complete, only seen when hypomorphic, typically asssociated then with developmental delay. Not all defects predispose to infections. May also exhibit cytopenias and malignant potential. Radiosensitivity tests are non-specific (and negative in RAG mutations).
Ataxia Telangiectasia - drooly face characteristic. Telangiectasia tends to come later. Variable immunodeficiency, typically ENT/airway problems. NB do not confuse dysarthria with cognitive impairment - may be intact.
Others are Nijmegen Breakage Syndrome, Bloom syndrome.
An immunodeficiency due (in 50% of cases) to SLAM associated protein (SAP) defect, specifically affecting the handling of EBV, affected boys are normal until they meet the virus. Following infection, they develop profound secondary immune deficiency affecting T and NK cell function and antibody responses. The following clinical patterns (not mutually exclusive) are described (and can be presenting features):
The prognosis is very poor with 75-85% mortality. Confirmation of the diagnosis involves demonstrating EB virus genome in lymphocytes by DNA hybridization, without antibody response to EB nuclear antigen (EBNA). The mothers of affected boys also have abnormal EB virus serology, with persisting very high titers against viral capsid antigen. Treatment is with Rituximab (anti CD21). If diagnosed in a sibling before they the virus, regular IVIG as passive immunization can be attempted though its efficacy is unproven.
Autosomal forms have been described.
This condition is characterized by chronic candidal infection of skin, nails and mucus membranes. It is almost certainly made up of a heterogeneous group of conditions of varying severity and of varying inheritance. Features:
Secondary causes are burns, protein losing enteropathy (eg CCF), nephrotic syndrome. Rituximab should not cause, because it does not target plasma cells!
Primary causes are:
85% of patients with early-onset hypogammaglobulinemia and absent B cells are male and have XLA or Bruton's disease (mutations in tyrosine kinase gene, BTK or Bruton's tyrosine kinase). A number of distinct mutations of the Btk gene have been described, contiguous gene involvement is thought to be responsible for deafness (Mohr-Traenbjaeg syndrome).
Onset of recurrent bacterial infections is typically towards end of first year of life as maternal antibodies passively acquired through the placenta fall. The sinopulmonary tract is a frequent site of infection, other sites are pyoderma, chronic conjunctivitis, gastroenteritis, arthritis (20%), meningitis-encephalitis (16%), and, less commonly, osteomyelitis (3%) and septicaemia (10%). Poorly treated pulmonary infections eventually lead to bronchiectasis.
Typical bugs are Pneumococcus, Staph, Haemophilus, Pseudomonas, Mycoplasma hominis, Campylobacter fetus, Neisseria meningitidis.
Because cellular immunity is intact, most viral infections, fungal infections, and tuberculosis are not a problem, except enteroviruses (eg disseminated polio, chronic enteroviral encephalitis) and viral hepatitis. Giardia lamblia is a particular problem. Pneumocystis jiroveci infection is rare but can occur.
Lymphoid tissues (eg, adenoids, lymph nodes, and spleen) are reduced in size, unlike tissues in patients with common variable immunodeficiency (CVID). A dermatomyositis-like syndrome can also occur, with or without chronic encephalitis, manifestations of chronic enterovirus infection. Vaccine-associated poliomyelitis can also occur in patients with XLA. Autoimmune disorders do not seem to be a frequent problem in patients with XLA, unlike in patients with CVID. Not clear whether patients with XLA have the same predisposition for malignancy as other patients with immune deficiency.
Early diagnosis, broad-spectrum antibiotics, and replacement therapy with IVIG has changed the outcome of this disease. Infections, especially chronic enteroviral infections and chronic pulmonary disease, are still the 2 major complications in XLA. Quatier's retrospective study reported that early IVIG replacement therapy and trough IgG levels of greater than 500 mg/dL were important in preventing severe acute bacterial infections and bronchiectasis. Trough levels of greater than 800 mg/dL may be necessary to fully prevent chronic sinusitis, bronchiectasis, and enteroviral infections.
BTK is part of pre-B cell receptor signalling. There is a total absence or marked deficiency of serum Igs. Percentages of circulating B cells are extremely low (<2%) or absent. However, pro-B cell numbers in the bone marrow are normal or even increased in number. T lymphocyte counts etc are normal. Lymphoid tissues show absence of plasma cells, lymphoid follicles, and germinal centers. Some patients with Btk mutations may not present until later in life which may reflect different types of Btk mutations with partial Ig synthesis. A subgroup of patients with CVID may also present with profound hypogammaglobulinemia and markedly reduced numbers of B cells.
Girls presenting with absent B cells and agammaglobulinemia had more severe disease than the boys with Btk mutations.
No response to vaccines, but worth trying? Not OPV, of course.
Mainly boys (55%-65%), severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE but elevated IgM levels. The defect is in CD40 ligand , which is one of the main activating receptors on T cells meeting antigen presenting cells (including B cells), hence there is a combined defect which can also lead to autoimmune disease (esp haematological). The defect means that Ig class switching cannot occur; hence IgM (which is the basic Ig produced) is present at normal levels to begin with, but IgG and IgA are very low, and in response to infection levels of IgM begin to rise markedly (may reach 1000+ mg/dL!). B,T-cell numbers and proliferative responses are normal.
The gene defect in the autosomal variant (HIGM2) is in activation-induced cytidine deaminase (AID) or Uracil nucleoside glycosylase (UNG). Both AID and UNG are nucleotide modifying enzymes expressed only in B cells and used for class-switching. Infections usually start a bit later than in patients with HIGM1. Pneumocystis and autoimmune disease unusual, cf X linked, which makes sense since it is B cells rather than T cells that are affected. Lymphoid hyperplasia and adenopathy characteristic, unlike XLA.
High mortality in young adulthood (as seen in other immunodeficiencies too, related to compliance with prophylaxis?) so transplant if possible.
A rare form of X-linked HIGM syndrome is associated with hypohydrotic ectodermal dysplasia but these patients did not have opportunistic infections.
This is a rare, autosomal dominant (sporadic) immunodeficiency characterized by:
and bony abnormalities:
Also called Job's (because of the Bible story, smitten by boils etc, but sometimes confused with CGD) or Buckley syndrome. = STAT3 defect, part of IL6 receptor. Not an immunoglobulin problem but if antibiotic prophylaxis is inadequate, IVIG is sometimes used.
in neutrophil chemotaxis.An autosomal recessive form without the bone abnormalities but with vasculitis esp CNS involvement described.
A genetic periodic syndrome (see Periodic Fever below), not an immune deficiency syndrome. IgA often high!
A heterogeneous group of disorders involving both B-cell and T-cell immune function, but the predominant manifestations are:
Variable age at presentation, degree and type of hypogammaglobulinemia. The average age of onset of symptoms is 25 years!
The serum Ig levels are markedly diminished but are usually higher than those found in patients with XLA. Any or all isotypes of Ig can be affected, thus the term dysgammaglobulinemia. Specific antibodies are absent or reduced. B cells usually normal. T-cell function can be quite variable.
Lots of different immune deviations and presumably causes eg inducible T-cell costimulator gene (ICOS, people from Black Forest). Family members of patients with CVID have an unusually high incidence of IgA deficiency, autoimmune diseases, autoantibodies, and malignancy.
One of the most common antibody deficiencies, incidence 1 in 400-3000. Defined as a serum IgA concentration of less than 7 mg/dL with normal serum IgM and IgG levels. Both IgA subclasses (IgA1 and IgA2) are usually markedly reduced or absent, although isolated deficiencies of each subclass have been described. IgA deficiency may be found in association with other immune abnormalities, including ataxia-telangiectasia and IgG subclass deficiencies (although subclass deficiencies do not seem to have any clinical associations). May occur in association with drugs (phenytoin, sulfasalazine, hydroxychloroquine, and D-penicillamine), chromosomal abnormalities (esp chromosome 18). In some families IgA deficiency appears to be inherited as a recessive trait, whereas in others it appears to be dominant with variable penetrance.
Many individuals with selective IgA deficiency are clinically asymptomatic. Those IgA-deficient patients with symptoms have sinopulmonary infections and involvement of the gastrointestinal tract with giardiasis and nodular lymphoid hyperplasia. Increased frequency of autoimmune disorders including arthritis, a lupus-like illness, autoimmune endocrinopathies, chronic active hepatitis, ulcerative colitis, Crohn's disease, a sprue-like disease, and autoimmune hematologic disorders. Selective IgA deficiency is strongly associated with atopy. The variability in clinical expression may be related to the compensatory increase in secretory monomeric IgM or associated IgG2/IgG4 or IgG4 subclass deficiency.
IgA-deficient patients are at risk for the development of anti-IgA antibodies on receipt of blood products. Precaution must be exercised in the administration of IVIG for replacement of IgG subclass deficiency in IgA-deficient patients because IVIG preparations contain small amounts of IgA. However, this risk does not appear to be a problem in those patients with partial IgA deficiency (ie, IgA levels >2 SDs below the normal value for age but greater than 7 mg/dL).
Pathogenesis of IgA deficiency is presumably abnormalities in Ig class switching. T-cell function normal in most.
Some infants have an abnormal delay in the onset of Ig synthesis, such that the normal physiologic hypogammaglobulinemia that occurs between 2 and 4 months of age is exaggerated and prolonged. This exaggerated physiologic hypogammaglobulinemia may occasionally extend into the second or third year of life. Affected patients usually have recurrent upper respiratory tract infections, including otitis media, sinusitis, and, less commonly, pneumonia. Serum IgG and IgA levels are usually low, but the IgM level is normal or increased. Circulating Ig+ surface lymphocytes are normal. Antibody responses to protein antigens are normal, but the antibody response to viral respiratory agents may be reduced. Recovery occurs between 18 and 36 months of age, but long-term follow-up necessary to rule out primary immune deficiency disorders, such as CVID.
Clinical significance controversial! A low IgG1 does not occur in isolation. Low IgG2 is associated with an increased risk of bacterial infections but only in some individuals and not in others! Isolated IgG3 and IgG4 deficiency have not been convincingly demonstrated.
The age at which each of the IgG subclasses reaches adult levels varies. In children IgG2 deficiency is the most prevalent (cf IgG3 in adults). IgG subclass deficiency may be part of a broader immunodeficiency eg ataxia-telangiectasia, IgA deficiency (occurs in 15%), can be single IgG subclass deficiency or 2+ (eg IgG2 and IgG4 deficiency). Can be associated with recurrent infections of the upper and lower respiratory tracts, pathogens are generally limited to bacteria and respiratory viruses. Because IgG2 is important in the response to polysaccharide antigens, typical infections are with H influenza or S pneumoniae, and susceptible patients are unable to produce specific antibodies after immunization with purified (unconjugated) polysaccharide antigens (eg, Pneumovax). Those individuals with IgG2 subclass deficiency who are asymptomatic, on the other hand, may display shifting of antibody response to another IgG subclass or Ig isotype, which compensates for the selective IgG subclass deficiency. Also, antibody responses to a conjugate polysaccharide vaccine occur mainly within the IgG1 subclass instead of the IgG2 subclass.
The best test, therefore, is specific antibody to Hib or Pneumococcus, with or without immunization.
Some patients with normal Ig and IgG subclass concentrations have poor responses to immunization with (unconjugated) polysaccharides eg Hib capsular antigen, or pneumococcal polysaccharide antigens. Immunization with conjugate vaccines (Hib or pneumococcal) may be helpful eg patients with recurrent acute sinusitis, because antibody responses to conjugate polysaccharide vaccine tend to fall within the IgG1 subclass instead of the IgG2 subclass. Selective antibody deficiency appears to be a disorder of young children eg 3-6 yrs, ?maturational delay.
Characteristic microthrombocytopenia, so look at film! Immunodeficiency is not just T cell, more complex. Eczema, autoimmune disease, lymphoreticular malignancy. A cytoskeleton disorder, caused by WASprotein deficiency, used for chemotaxis by actin manipulation, and similarly cell division by contractile ring formation. Part of a spectrum, mild end is X linked thrombocytopenia, +/- eczema, immunodeficiency. Clinical scoring system by Ochs.
Most de novo, no sex diff, more than 80 clinical features. Most have 22q11.2 deletion - do FISH to diagnose. The TBX1 gene coding for T box-1 transcription factor; is located here and in cases without deletion mutations in this gene are sometimes but not always found. Pharyngeal pouch & neural crest migration disordered.
CATCH - Cardiac, absent Thymus, Cleft, Hypocalcaemia is a clinical mnemonic, but there's more!
Severe immunodef eg mucocutaneous candida, PCP, viral, graft vs host rare and only seen in the minority (25%) who have no thymus at all (Complete DiGeorge)- of those, most will have microscopically). Complete cases have a SCID like disease. Partial cases also have T cell deficiency: the count usually increases through the first 1-2 years of life but not to normal range. Ig totals usually OK but specific may be poor.
In theory live vaccines should be avoided, and measles/varicella prophylaxis offered after exposure. But 2 retrospective studies of children with partial DiGeorge (ie thymus present) who were immunized pre-diagnosis did not find any complications! Irradiated blood products. Conj pneumococcal vaccine. Average IQ 75 so many normal. Increased risk of schizophrenia! Autoimmune probs (Graves, eczema, aplastic anaemia, Evans) occur, presumably due to abnormal T cell regulation. Differential diagnosis of facies is Smith Lemli Opitz, Goldenhar, Digeorge 2 (cytogenetic deletion, more severe facies, chromos 10).
Family support at vcfs.net
Asplenic patients are at increased risk for life-threatening infections, most commonly Strep. pneumoniae. The level of risk appears to correlate inversely with the amount of time a patient has had a functioning spleen, so adults post-splenectomy for trauma have a lower risk of serious infection than infants with congenital asplenia syndrome. Children who undergo splenectomy as part of treatment for malignancy are at great risk. Approx 5% of children whose spleens are removed before the age of 4 years have significant infections, with a mortality rate of 30% to 60%. Risk is greatest in the year after splenectomy and continues to be significant for the next 7 to 10 years, after which risk is low but never as low as for patients with normal splenic function.
Polysplenia syndromes (eg Ivemark syndrome) also have increased risk. Splenic function should be evaluated in children with congenital abnormalities of embryonic lateralization, such as:
Asplenia and polysplenia are often associated with other types of congenital abnormalities, including gastrointestinal malformations such as:
Functional asplenia is confirmed by the presence of Howell-Jolly bodies in a peripheral blood smear (obtained after the first week of life), absence of splenic uptake on a technetium99 sulfur colloid scan, or increased percentage (more than 3%) of pitted or pocked erythrocytes in peripheral blood. The last test is a useful means of monitoring splenic function.
Encapsulated organisms represent the greatest risk - S. pneumoniae has been associated with 50% to 90% of the overwhelming infections occurring after splenectomy. Other pathogens are H. influenzae b and N. meningitidis. Other streptococci, such as Streptococcus agalactiae (group B streptococcus) and Enterococcus spp., may cause mortality in asplenic hosts. Infections due to Salmonella spp. very important in sickle cell disease, also reported in asplenic patients but risk lower. Fulminant septicemia due to Capnocytophaga canimorsus (mouth flora of dogs) occurs. Probably an increased risk of gram-negative bacilli but ?underlying malignancy, immunosuppression, and chemotherapy. Higher risk for Babesia microti (a tick-borne plasmodium-like parasite endemic off the coast of Eastern United States) - whether greater risk of severe infection from Plasmodium species is not well-established.
Immunization with conjugate pneumococcal and Hib vaccines as well as influenza & varicella vaccine is recommended for all asplenic children, with use of the polysaccharide meningococcal and pneumococcal vaccine after age 2 years (although the response to the latter vaccine is variable). For elective splenectomy, children should be immunized at least 2 weeks beforehand if at all possible. Children have a more rapid decline in antibody titers after pneumococcal vaccination and should be revaccinated at 3-to 5-year intervals with the 23-valent polysaccharide vaccine.
Most experts recommend penicillin prophylaxis for children who have congenital asplenia or who undergo splenectomy for hemolytic anemia, malignancies, or liver transplantation at any age; for those who undergo splenectomy before age 5 years; and in the first years after splenectomy for those who undergo the procedure at any age. There is no consensus as to when penicillin prophylaxis should be discontinued - doesn't seem to be as important as in Sickle cell disease. Equally, prophylaxis does not prevent all infections esp Hib.
Fever should be taken seriously: begin empirical amoxicillin therapy urgently. A third-generation cephalosporin is usually given unless clinical findings or setting requires broader consideration of potential pathogens.
Travel advice - avoid malaria zones, ticks in US, dogs. Meningococcal A polysacch vaccine? Emergency supply of amoxicillin. Primary care should give IM benzylpen if significant infection before transfer to hospital.
If lung disease, pulmonary function testing should be performed at least once every 6 months; sputum cultures should also be obtained routinely. High-resolution chest CT may identify early bronchiectasis. If diarrhoea, stool examinations esp G lamblia and Campylobacter and Yersinia species. G lamblia responds to metronidazole, as does bacterial overgrowth of the small bowel. NB risk of Clostridium difficile in patients on chronic antibiotic therapy. Blood chemistries, including hepatitis screens and liver function tests, should be obtained on a regular basis (every 6 months or yearly). Blood counts and differentials should be determined at least every 6 months because some patients, such as those with CVID, may have autoimmune cytopenias. A physical examination for abnormalities of lymphoid tissues in patients with CVID is important for surveillance of lymphomas.
Serum Ig concentrations should be measured, compare with normal values for age. IgG subclasses may be helpful (but debate about significance, see above) - a careful history and physical examination are important to determine the clinical significance of an Ig subclass abnormality. In addition, the measurement of functional or specific antibodies is critically important to determine the clinical relevance of an Ig deficiency.
Isohemagglutinins (naturally occurring IgM vs ABO blood groups) appear by 1 year of age in 70% of infants, depending, of course, on their blood type. One can assess the production of specific antibodies after immunization with tetanus, diphtheria, pneumococcus, and other vaccines. Responses to protein antigens generally fall in the IgG1 subclass, whereas the immune response to polysaccharide antigens resides within the IgG2 subclass (unless conjugated, so not helpful for assessing IgG2). Because recurrent upper respiratory tract infections are common, test serum for the presence of antibodies to common respiratory viral agents, such as influenza A and B, mycoplasma, respiratory syncytial virus, adenovirus, and the parainfluenza viruses. These antibodies fall into both the IgG1 and IgG3 subclasses.
Flow cytometry reports numbers of B cells and their expression of surface Ig in patients: less than 2% B cells (CD19+) will need further molecular evaluation for Btk mutations, or abnormalities in the pre-B-cell receptor complex and secondary intracytoplasmic signing pathways. Approximately half of the patients with CVID may have reduced T-cell numbers and diminished lymphocyte proliferative responses to mitogens and antigens.
Antibiotics and chest physiotherapy are very important. IVIG has been a major advance in the treatment of patients with antibody deficiencies. Newer IVIG products have additional viral inactivation steps. IVIG comes in 3&10g bottles. Dosage regimens range from 300 to 600 mg/kg every 3 to 4 weeks. Roifman et al showed that doses of 600 mg/kg every 4 weeks achieved serum IgG troughs of greater than 500 mg/dL. Even higher doses may be necessary for patients with severe chronic sinopulmonary infections and to prevent bronchiectasis. Serum IgG trough levels need not be measured with each infusion. After a dose change, equilibration of the serum IgG level may take 3 months. Success of replacement judged by:
Most adverse reactions are related to the rate of infusion and can be controlled by careful monitoring and slowing the rate when necessary. Other symptoms unrelated to rate can often be controlled by means of pretreatment with paracetamol or nonsteroidal anti-inflammatory drugs. Adverse reactions : aseptic meningitis (15-20%! Immune reconstitution reaction?), anaphylaxis (anti-IgA antibodies in IgA-deficient patients - an IVIG preparation with a very low level of IgA contamination should be used instead), haemolysis, hepatitis.
IL-2 might be useful as adjunct therapy in some patients with CVID, but further studies are needed to determine whether this type of treatment results in fewer autoimmune disease and malignancies. Unlike T-cell immune deficiencies, bone marrow transplantation and gene therapy have not become important therapeutic modalities in antibody deficiencies thus far.
If CD4 under 200, give PCP prophylaxis ie Co-trimoxazole (Septrin) 3 times weekly. NB bone marrow dyscrasia, Stevens Johnson syndrome as side effects. Else Pentamidine, Azithro (3x weekly).
No live vaccines, Measles/varicella prophylaxis. Irradiated blood products. Conj pneumococcal vaccine, Influenza vaccination in October/November.
Beta Lactam monotherapy as effective as combination therapy for fever and neutropenia, plus less adverse effects. systematic review in adults, BMJ 2003
Ciclosporin for GVHD prophylaxis, aciclovir/septrin/itraconazole prophylaxis, beware VZV/measles (could get immunoglobulin), CMV/EBV/adeno weekly screening, weekly chimerisms (to monitor uptake of transplant). Human herpesviruses usually relapse in blood (on PCR) first before appearing in organs. Only exception is CMV pneumonitis reactivation which may not be obvious in blood. Adenovirus probably reactivates from gut colonization.
Cardiac/renal screening (EDTA) at intervals, IVIG regularly for 1 year then stop. If levels maintained then immunize. Give MMR @2yrs.
High risk of TB reactivation, often atypical eg PUO, organ dysfunction.
Not much evidence from controlled studies, mostly expert opinion! Beware transmission of live vaccines from siblings (MMR, BCG excepted). Very unusual to be so immunocompromised that you get no benefit!
| Infectious causes |
| Mycobacteria (TB and non-tuberculous disease) |
| Borrelia |
| Leptospira |
| Streptobacillus moniliformis (rat bite fever) |
| Hepatitis B |
| Orbivirus |
| Rickettsea (typhus) |
| Entamoeba histolytica |
| Others |
| Cyclical neutropoenia |
| PFAPA |
| Behcet's |
| Hyper IgD |
| Familial Mediterranean fever |
| Familial Hibernian fever |
Periodic fevers are defined as uniform periods of fever that recur regularly in individuals who are healthy between attacks. Parents may organize life eg holidays around expected attacks and don't have any concerns otherwise cf child with recurrent respiratory and gastrointestinal infections after starting nursery who "always has something". Recurrent bacterial infections esp recurrent/chronic pneumonia or otitis media may indicate a humoral immune defect. Similarly, recurrent documented viral or fungal infections may indicate a cell mediated immune defect.
Regular pattern of fever, approximately three-weekly, perhaps associated with malaise, periodontitis, aphthous ulceration, impetigo, sore throat and enlarged lymph glands (elastase defect). But by the time the child presents, the neutrophil count may have returned to normal (although unlikely to be high). Check FBC twice weekly for 4-6 weeks to demonstrate the fluctuation of the neutrophil (and monocyte) count. NB important not to miss, as children can develop severe bacterial sepsis while neutropaenic (mortality rate of up to 10%). Need antimicrobial prophylaxis, and possibly GCSF. Differential is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) - fever every 4-6 weeks, neutrophil count normal, headache, cervical lymphadenopathy, musty smell, abdo pain. Affected children continue to grow normally, are well between attacks, and do not suffer long-term sequelae. Treatment with steroids or with cimetidine has been effective, and some children have had no further attacks following tonsillectomy (ie chronic strep infection).
Behcet's syndrome may also be associated with fever and aphthous stomatitis. However, there is no regular periodicity of the symptoms, and episodes of fever may last for weeks. Other features - arthritis, genital ulcers, iridocyclitis, and skin rashes (incl erythema nodosa). Gastrointestinal and central nervous system complications may occur.
Short attacks of fever, usually lasting 1-3 days, recurring at varying intervals. Most children develop severe abdominal pain with the episodes, due to sterile peritonitis. Pleuritis, leading to chest pain, arthritis, myalgia and skin rashes may also occur. Most cases are from Arabic Turkish, Armenian or Jewish background. Inheritance is autosomal recessive. The gene has been cloned and four mutations have been identified. Colchicine is the treatment of choice. Some patients may develop amyloidosis; certain mutations are at higher risk.
First described in a family of Irish descent, now called TRAPS (TNF receptor assoc periodic syndrome), and now described in a wide range of different ethnicities. Various mutations of TNF-Receptor Super Family 1A (TNFSF1A) seen, on chromosome 12p (same as HIDS but different gene). These mutations are dominant and penetrate poorly, with only a small proportion developing disease.
Onset is typically around 3yrs of age but varies widely. Periodicity also varies widely: typically every 5-6 weeks. Fever for 3 days heralds onset of other symptoms, which then last for usually 5 days or more (cf FMF):
About 14% develop amyloidosis. Etanercept appears to prevent; colchicine does not. 12352631
Mostly Dutch and French. Big database in Nijmegen. A genetic syndrome (autosomal recessive, explained by MVK gene mutations on chromosome 12p - see Omim) with recurrent febrile attacks starting under 1yr of age. Attacks last 3-7 days, so may or may not be shorter than TRAPS, occur every 4-8 weeks. Features are:
Diagnosis is by finding of high IgD (>100U/ml); most also have high IgA (with or without raised IgG and IgM), which is an important clue. Increased Mevalonic acid in urine during fever. Febrile attacks in response to immunizations often reported, so may be another clue. Attacks tend to diminish with age without completely disappearing; amyloidosis seems to occur only rarely (cf TRAPS). Simvastatin is supposed to help!
A Cryopyrin disorder, found in Northern Europeans. Attacks are very brief eg 1-2 days, apart from fever, an urticarial rash is seen (unusual), limb pain/arthralgia occurs. Abdominal pain and arthritis occur rarely. Sensorineural hearing loss is characteristic. Amyloidosis affects 25%, which is high cf other periodic syndromes. Steroids are often used but benefit is inconsistent.
Familial cold autoinflammatory syndrome (FCAS) is a similar condition, also related to Cryopyrins. Cold induced obviously, but without the deafness, and amyloidosis is rare.
NOMID/CINCA are also related - the names say it all: Neonatal onset multisystem inflammatory disorder, chronic infantile neurological cutaneous and articular syndrome. Papilloedema and uveitis potentially leading to blindness occur; there is epiphyseal bone formation; hepatosplenomegaly; and a chronic meningitis with deafness. There is no known treatment, sadly.
Meta-analysis has demonstrated benefit of enteral immunonutrition in surgical/critical adult patients: various combinations of arginine, n-3 fatty acids, nucleotides and/or glutamine. Led to reduced infections and length of stay although no reduction in mortality.
Enteral glutamine has been shown to reduce sepsis in neonates.
Role for TH1 cells, autoantibodies and cytokines - eg inappropriate T cell activation leads to activation of macrophages with release of proinflammatory cytokines eg TNF alpha and IL1, and/or antibody production.
Green book page at DOH has latest updates on immunization advice for UK in PDF format. My PDA friendly but incomplete web version is here.
UK is moving to acellular pertussis (3 or 5 antigens cf 3000 in whole cell), so less reactions (but less effective and immunity shorter lasting); and IPV (injectable) instead of OPV (oral, live, Sabin) polio vaccine - same efficacy, no vaccine associated disease. These newer vaccines have fewer reactions, and do not contain thiomersal. Not that there's any evidence against mercury, but plan to eliminate it has been in place for several years. There was also an issue with loss of Hib efficacy when using 3 in 1 DTP, which is not seen with Pediacel. At preschool booster time, Pediacel can be given or else a low dose Diptheria combined product (Infanrix IPV or Repevax) so long as primary course was completed.
Instead of BCG for all adolescents, risk factor approach introduced: BCG will be offered to all infants in health boards with incidence over 40/10 000 (none in Scotland), and to those with parent or grandparent from high incidence area.
Antibody tests for immunity are available but unreliable, because measure circulating levels and do not take into account potential for memory. If positive then the patient probably has been exposed or immunized but you still don’t know if the course was completed or if the vaccine was of adequate quality. If in doubt, reimmunize from the beginning - hypersensitivity (ARTHUS) reactions are v rare in young children and are probably related to impurities in older vaccines.
Prenatal or early neonatal immunization would be nice, but poor responses - Due to poor IL12 synthesis, poor antibody response (poor germinal centre reaction, where follicular dendritic cells present antigen), interfering maternal antibodies (less of a problem with conjugated vaccines), plasma cells not surviving long term in bone marrow.
Polysaccharide capsule, as found in meningococci and pneumococci is resistant to complement, hence a useful virulence factor. Antibody vs polysaccharide is effective put poor production under 2 years of age (delayed maturation eg marginal zone of spleen). Plus, response is restricted to IgG2, ie no surface antibody, and no memory as T cells not involved (some evidence that adolescents do produce memory to natural exposure, at least to some polysaccharides).
To get around these problems, Conjugate vaccines have been developed, in which tetanus toxoid or other stimulant protein eg CRM197 is covalently linked to the polysaccharide antigen, which together induce a T cell dependent response (recruits class II MHC and T helper CD4 cells), which therefore produces better antibody levels in infancy as well as memory.
Strangely, acellular pertussis given concomitantly reduces immunogenicity, probably aluminium adjuvant binds to polysaccharide and hides it.
Amount of protein carrier critical - bell shaped curve of immunogenicity. These vaccines are effective but expensive, hence are rarely used in developing world.
With time antibody titres do fall, but memory usually persists and antibodies may be high affinity anyway so levels alone are not a good indicator of immunity.
Hyporesponsiveness – second immune response to vaccine less good than first… ?why.
See MMR the facts NHS website. No support for measles PCR in CSF or gut (but data under court order). Previous studies discredited.
No increased risk of developmental regression retrospectively (Lancet, Taylor B)(NEJM, Madsen). No ecological association (UK, California). No new bowel - autism disorder.
Infant immune system can respond to >10-000 antigens (Peds, Offit), actually less infections post vaccination cf controls (Arch, Miller)!
Should NHS provide inferior service for sake of parental choice? Single vaccine policy - ask about license? How many doses? Which manufacturer? Cold chain? etc.
IgM saliva test from Colindale. No great outbreak seen so far since fall in coverage but high proportion of vulnerable infants hence risk of SSPE later (who have atypical acute infection).
2nd dose essential. With 1 dose, 90% efficacy only so gradual build up of susceptibles leading eventually to an epidemic eg Poland.
BCG is a really old vaccine, developed in 1921. Its popularity has waxed and waned - trials have shown almost zero benefit against pulmonary disease in high prevalence areas, presumably due to the presence of related mycobacteria in the environment. At the same time, the disease is not the killer it once was. But it is still 75% effective against miliary TB and meningitis in children; and the stakes have changed now with the advent of AIDS. Some countries that discontinued routine vaccination have had outbreaks of TB meningitis. It is also effective against leprosy.
Worldwide, BCG prevents one case tuberculous meningitis for every 3500 vaccinations, and one case miliary tuberculosis for every 10 000 vaccinations. Lancet. 2006 Apr 8;367(9517):1173-80
Should you do Heaf test first? No RCTs for BCG vaccination with vs without Heaf testing. In people with TB, vaccination leads to induration > 5mm within 24-48 hours (sometimes within 6-12 hours, occasionally slower but still with pustule formation at 5 days cf 2 weeks). This reaction seems to be more reliable than the Mantoux test. No complications reported. Necrotic reactions are associated with previous BCG vaccination.
Already a recent and substantial increase in resistance to erythromycin and clindamycin among GBS has been documented by several groups of investigators. Maternal immunisation with an optimally immunogenic GBS vaccine during the third trimester should protect neonates and young infants from invasive GBS infection during the age of risk. Five serotypes (Ia, Ib, II, III, and V) account for virtually 100% of GBS disease in infants and adults, The emergence of type V and an increasing number of nontypeable GBS isolates from colonised adults underscores the importance of ongoing epidemiologic investigations.
Conjugate vaccine using PRP antigen from capsule.
HIB vaccine initially led to reduction in invasive disease throughout population, presumably through herd effect, but this has not been sustained, in fact antibody levels are falling among older people, suggesting fewer opportunities for boosting immunity.
Natural tendency for antibody levels to decline in childhood, which makes effective memory response critical (disease is still rare). After Hib meningitis there is evidence of improved antibody levels, consistent with a priming effect.
Big gap between the evidence and the national policies. Overall 79% protective vs infection. But systematic reviews show little or no effect on mortality, even in the elderly (although bizarrely all cause mortality was reduced - probably cohort bias). Most studies are of poor methodological quality and the impact of confounders is high. In Japan, school based immunization reduced deaths significantly but they had higher baseline death rate cf US.
In kids, highest hospitalization rate seen in infants too young to vaccinate, and no data on efficacy in under 2s. Effective vs flu acute otitis media (AOM), but only 3-4% of AOM. Antibody levels in young do not rise much. SE headache, rhinorrhoea… NO exacerbation of asthma despite initial concern, thankfully. Cheap cf other vaccines, but you have to give it every year.
No benefit in asthma (Cochrane), no benefit in CF (but poorly controlled).
Presumably the problem is availability creep, where countries prefer to invest in an available technology rather than invest in testing it. Then it becomes much more difficult to randomize. BMJ 2006;333:912-915
Intranasal live atten vs inact was 66% protective over 3yrs, but not obviously better under 3yrs (indeed, more wheeze and hospitalization in 6-11/12). Belshe NEJM 2007
Intradermal route effective for influenza vaccination, uses less, and may produce better immunity in certain groups eg elderly hence ideal for pandemic. Works via intradermal dendritic cells which induce cell mediated immunity esp CD4 and 8, plus enhance antibody production via CD4.
91 serotypes but about 15 cause vast majority of disease worldwide. Different serotypes are seen more or less commonly in different countries. Some serotypes are cyclical or produce outbreaks eg surge in 1 & 5 in Sweden in late 90s (more assoc with developing countries, penicillin sensitive), similarly Chile in early 2000s. The ones that produce the most disease are also the ones seen most commonly in younger children, and are the ones most associated with penicillin resistance.
2 vaccines at the moment, more on the way. 23 valent polysaccharide vaccine was first, not much response under 2 yrs. 7 valent conjugate vaccine (PCV7) is now part of universal schedule in UK, given at 1 and 3 months, with booster in 2nd year. Doesn't cover as many strains, but more immunogenic in the young. Regimen depends on age as immunogenicity varies at different ages. Manufacturer recommends 4 doses if under 6/12 (from 2 months old, 3 doses a month apart, then booster), 3 doses if 6-12/12, 2 doses at least 2/12 apart if 1-2yr, single dose if over 2yr. Booster in second year v important. Then give Pneumovax from age 2yr (leave 2 months from last conjugate). Over 5 yrs, Pneumovax (23 valent), single dose (unless asplenic or nephrotic).
Social mixing viz siblings, day care enhances response to PCV7: priming to pneumococci by natural polysaccharide exposure?
Since universal introduction in US 1999, significant reduction in invasive disease (90% less vaccine types), also 56% reduction in adult disease due to herd immunity (73% reduction in vaccine type pneumonia in >65s, 2x as important numerically as benefit in vaccinated children!). Significant reduction in AOM in US surveillance, possibly reduction in pneumonia (wide confidence limits, data not up to speed). In Italy, less antibiotic courses, less AOM and pneumonia.
Bizarrely, 39% reduction in US of all cause pneumonia in <2yr, which in absolute numbers is 20x as important as 65% reduction in pneumooccal pneumonia. Unexpected benefit on non-pneumococcal LRTI incl bronchiolitis and NPA pos pneumonia. (Grijalva, Lancet 2007). In Gambia trial of PCV9, 16% reduction in all cause mortality!
84% of UK invasive disease serotypes covered by PCV7. Fear that vaccine serotypes may be replaced by nonvaccine ones (although they would be less resistant) - US has seen an increase in 19A invasive disease; Alaska has seen increase in invasive pneumococcal disease among native Alaskan children under 2 yrs by 82% since 2001 Singleton, JAMA 2007. Replacement will presumably worsen with better coverage. But these kinds of studies are confounded by having dissimilar groups and antibiotic pressure effects.
New conjugates eg SYNFLORIX (=PCV10 + H influ protein D). Prevnar 13 due in next few years. PCV7 coverage less good in Europe (66-80%) cf US (>80%) and <50% in Russia, China. But PCV10 etc would achieve >80% in most of world. Plus they may be better at achieving mucosal immunity (hence reducing carriage).
In UK, recommended for asplenism (incl coeliac!), chronic lung disease (not asthma unless on regular systemic steroids), at risk for aspiration, congenital heart disease (def!?), chronic liver & renal disease (incl nephrotic), diabetes on insulin (!), immunosuppressed (incl HIV), cochlear implants, CSF shunts, under 5s with previous invasive pneumococcal disease. CMO letter 30 Jun 05
Meningococcus is hugely complicated bug, even more than HIV. Not described until 1800s, perhaps reflecting a recent adoption of the polysaccharide capsule. Five serogroups (A, B, C, Y and W-135), are responsible for disease.
Age distribution varies too eg B dominates in infancy. Children under 5 have the highest attack rates; a second peak in incidence occurs in persons ages 15-24 years (esp students in halls), probably related to behaviour eg kissing, socializing. Higher case fatality rates occur in the older group (20% in the US in 2002).
Complement forms membrane attack complexes vs Neisseria meningitidis, which are protective if you have the triggering antibody, but these responses are age-dependent and do not induce memory (T cell independent). Polysaccharide vaccines against groups A and C were safe and effective (in fact Men A is immunogenic from 3 months of age), but group C is not only poorly immunogenic in infants but immunity rapidly wanes off (also evidence that repeated doses cause immune tolerance to polysaccharides). Can be used to control outbreaks and protect high risk persons; at least it does not apply selection pressure. Quadrivalent polysaccharide vaccine vs A, C, Y and W-135 polysaccharides (Menomune) has been licensed in the over 2s. Menactra (also ACYW135) for adolescents, not v effective in infants plus 17 reports of Guillan Barre; plus it costs $70-80/dose, so probably just for outbreaks and travellers to epidemic areas.
Conjugate vaccines not only provide better responses with memory, they also prevent acquisition of nasopharyngeal carriage, thus inducing herd immunity. The UK introduced group C meningococcal conjugate vaccine into immunization schedules in 1999. Concerns that meningococci would switch their polysaccharide capsule under ecologic pressure have not been borne out (although more group B in New Zealand) - good herd immunity too. But geometric mean titre (GMT) antibody levels fall to baseline by 4yr; not strictly indicative of protection, indeed, memory seems to persist. Modelling by Ray Borrow (HPA Manchester) suggests that there may be a gradual rise in cases, so schedule may need to include a booster (?reduce 3 doses in infancy to 1 , nearly as effective).
The group B polysaccharide capsule is near identical to tissue found in the developing fetal brain, so is identified as a self-antigen even after conjugation to a carrier protein and is not immunogenic. Group B surface proteins such as outer membrane proteins (OMP) and lipopolysaccharide (LPS) also have been studied as potential vaccine candidates.
Older, whole cell vaccines were highly effective but associated with side effects, particularly encephalopathy. Hence acellular vaccines used exclusively now. Eradication would need universal program of 10yrly boosters with a good vaccine eg acellular vaccine with multiple antigens, which are more effective and longer lasting (cf 2-5 yrs with standard vaccine).
France and Germany boost at 11-18 yr. Apparent rise in adolescent cases over last 20yrs but probably down to awareness and diagnostic methods rather than change in organism or influence of inferior acellular vaccine. Still, not a bad idea if aiming to prevent neonatal disease by ensuring immunity among young parents. Other strategies for preventing neonatal disease are targeting of parents/teachers/health care workers; immunizing pregnant women (ethically difficult); Cocoon strategy of immunizing new baby's parents/siblings. But these targeted strategies fail to prevent a lot of primary cases in older adults.
Immunizing neonates would not protect them but would prime them for the second dose.
Justification for universal programme:
Vaccine is a live atten Oka strain. 1 dose for under 13yrs, usually 2nd year (prevents 85% disease; 2nd dose would increase to 99% but would lose cost effectiveness). 2 doses for immunocompromised. 50m + doses in US since 1995, serious reactions rare (hepatitis, pneumonia, ?encephalitis). Break through varicella milder but can still be transmitted, if more than 50 lesions after vaccine, then same transmission risk as wildtype. Zoster due to vaccine does occur but more rarely than in wild virus infection.
Postlicensure, 80% prevention of mod/severe disease in outbreaks, in prospective studies over 90% prevention. Also reduction of disease in infants and adults by herd effect. Mean age of disease higher, so potentially more severe, but still less frequent than previous age-specific rate.
BUT: will lack of exposure to varicella in community reduce adult immunity and increase zoster?
New Quad vaccine (MMRV) - would restore cost-effectiveness for 2 doses!
4 common serotypes G1-4, G9 emerging. Various P types too, so some cross immunity. Rotashield vaccine in 1999 was effective but associated with intussusception and fever, so withdrawn. RIX4414 (Rotarix, G1P8) 2 doses (oral) gives 72/85% protection vs any/severe illness in Finland & S America. No risk of intussusception (?less!). Similarly for 3 dose pentavalent vaccine.
HPV quadrivalent vaccine - genotypes 16,18 cause 70% of Cx cancer (>99% are hpv related), the other 2 genotypes cover most genital warts. Poor public awareness. Need to immunise universally and in paediatric age group. HPV vaccine needs to be part of comprehensive system of cervical cancer prevention. Otherwise, parents who refuse to acknowledge reality of sexual activity by their children will forego vaccine. Making vaccination mandatory is appropriate in diseases where voluntary measures have failed, no less coercive alternatives exist, science is compelling and members of the general public unknowingly at risk. Not really true for HPV: parents who opt out need to have their concerns validated, while at the same time recognising that their child’s activities may differ from what they would approve of. Fear of increased promiscuity vs opportunity for parents to engage with children about sexuality. Legislation tends to engender resistance, as it reduces autonomy.
Palivizumab (Synagis) is a recombinant, humanised, mouse monoclonal antibody to the RSV fusion or F protein. Given intramuscularly, monthly 15 mg/kg IM over the RSV season to prevent bronchiolitis in the vulnerable. It carries no risk of viral transmission, and does not interfere with routine vaccination schedules. Indicated for (according to BNF):
It works, in that for congenital heart disease it gives a 45% relative reduction in RSV hospitalizations, a 56% reduction in total days of RSV hospitalization, and a 73% reduction in total RSV hospital days with increased supplemental oxygen. Non-significant reductions in ICU admissions or ventilation. PMID 14571236 . Impact trial found significant reductions for hospital admission (55%) for preterms with/without BPD, but again no definite benefit in ICU or ventilation PMID 9738173. Costs £2650 per patient per year. NNT vs admission =17 for Impact, 23 for CHD, which works out at £45 000 - 60 000 per admission prevented! Economics very dependent on rates of admission; sensitivity analysis suggests that the probability of admission would have to be 31% for it to break even. Archives of Disease in Childhood 2005;90:F286-FF289; pmid 16036888
HBV immunisation should be 0, 1, 6 months. An accelerated regimen of 0, 1, 2 months can be used where compliance is poor, but a booster after 12 months will then be needed. In the over 16yrs, an ultra accelerated regimen of 0, 7, 21 days can be used. The duration of protection is not known, hence a booster is recommended at 5 yrs (or with preschool booster for neonatal primary course). Anti-HBs >10 is protective, but >100 is preferred.
In congenital deficiencies, eg SCID, live vaccines are dangerous, but usually given before diagnosis! OPV is alright, but 1/3 given BCG will get disseminated disease, often fatal.
B cell def – can have measles, varicella, BCG (all T cell dependent). CD40 ligand def = B/T communication disorder. Might as well try!
HIV – CD4>300 have conserved immune responses, in adults anyway. Early immunization necessary but not sufficient to induce or maintain immunity. Tetanus is very immunogenic, diphtheria is less so (only 70% will be protected), measles similarly (only 55% protected). HAART prolongs immune competence but does not render normal even if aviraemic with normal CD4! Measles is safe, start at 9 months, ?repeat if poor response. VZV safe for asymptomatic, start at 12 months. BCG controversial, late dissemination described (Bull WHO Moss 2003;81:61)
Asplenia – prime with conjugate vaccines under 5 years, follow with polysaccharide vaccines. Above 5 years use polysacch but check responses, ?use conjugate if poor. Transplant/chemo – ideally vaccinate beforehand! Else accelerate course.
Steroids – the 1 month rule does not have much evidence to support it, so balance risk. Similarly for methotrexate, cyclosporin etc.
Relative/absolute contraindications for biological therapies are: (STOIC)
Peak action is about a week after infusion. The degree of bone marrow suppression probably reflects how well it is working...
Side effects - infection, bladder cancer, haemorrhagic cystitis, bone marrow toxicity and infertility.
Suppresses T cell activation and blocks IL2. Anaphylaxis has been reported to the IV form, but most of these cases have tolerated the oral form - presumably the carrier is the problem.
Interferon alpha, used for hepatitis B/C, has been associated with antithyroid antibodies, causing hypo as well as hyperthyroidism.
Monoclonal abs are either murine or human - but even 100% human proteins can be immunogenic because the technology introduces novel peptide fragments. Thus potential for decreased efficacy over time, hypersensitivity reactions (ie anaphylaxis, serum sickness, leukocytoclastic vasculitis, Stevens-Johnson syndrome and injection site reactions).
Side effects of monoclonals:
See Nutrition.
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PNP vs ADA