Which Lung Nodules Need Follow-up?

A 65 year old man who is a lifelong smoker undergoes low dose CT scan of the chest given recent onset cough and night sweats. The scan picks up a 8 mm nodule in the right upper lobe. Thoracic lymph nodes are not enlarged and there are no other lesions. How does one follow up?

The incidentally discovered solitary lung nodule must be one of the commonest problems faced by clinicians. Further, in the USA in particular, there is insurance coverage for low dose CT scannning of current smokers or ex-smokers aged 50-75 who have quit within the last 15 years, who have at least a 30-pack year smoking history. Studies have shown that such screening reduces lung cancer related mortality by 20%.

But which nodules do you ignore and which do you follow-up?

Studies conducted in smokers show that several factors predict risk of a cancerous lung nodule. Size is probably the most important. Nodules less than 5 mm carry <1% risk of cancer. This risk rises to 50% with nodules greater than 20 mm. A lesion bigger than 30 mm is classified as a "mass" rather than as a nodule. Other factors which increase risk of a nodule being cancerous are older age, female gender, family history of lung cancer, location in the upper lobe, emphysema, a part-solid rather than pure solid or ground glass (also called sub-solid) nodule and spiculation. The likelihood of cancer decreases when the number of nodules crosses four. Other factors also influence the likelihood of cancer being present. While most patterns of calcification are thought to favour a benign nodule, eccentric calcification increases the risk that the nodule is cancerous. Popcorn calcification is characteristic of hamartomas, while central calcification is usually benign. Peri-fissural nodules are almost always benign. Nodules which have been shown to grow on successive CT scans are clearly suspicious. However, the pace of growth matters. Most cancerous nodules have a "tumour-doubling time" between 20 and 400 days. Nodules which double in less than 20 days are likely to be infective. While most nodules taking more than 400 days to double in diameter on CT are likely to be benign, this does not apply to ground glass (subsolid) or part solid nodules. These lesions, particularly the subsolid nodules can only be picked up on CT, but not on chest Xray. Subsolid or part solid nodules can represent in situ adenocarcinoma, minimally invasive adenocarcinoma, lepidic adenocarcinoma, or carcinoid, are particularly common in non-smokers, and take longer to increase in size, with a tumour doubling time of up to 800 days. While solid nodules need only be followed up for 2 years, subsolid or part solid nodules need follow-up for 3 years. There is an on-line resource, available from Brock University, Canada, based on the Pan Can study which was then validated in a British Colombian cohort, which incorporates the above factors into a risk model. http://www.uptodate.com/contents/calculator-solitary-pulmonary-nodule-malignancy-risk-brock-university-cancer-prediction-equation?source=see_link&utdPopup=true Using the calculator, subjects are classified into 3 groups in terms of the likelihood that lung cancer is present <5% 5-65% >65%

With the lowest risk group, it is only necessary to do surveillance CT scans at algorithm determined intervals. The intermediate risk group should have a PET scan to assess the likelihood of cancer (>2.5 SUV being suspicious), while the highest risk group would have a direct non-surgical or surgical biopsy.

Normally, nodules less than 5 mm need no further follow-up unless they are part-solid. Larger solid nodules less than 8mm (called sub-centimetre nodules although the threshold is 8 mm rather than 1 cm), would need follow up up to 2 or 3 years depending on whether they are solid or subsolid. Nodules larger than 8 mm would ordinarily be scanned after 3-6 months, with repeat scans in 9-12 months and 18-24 months. If the nodule has grown more than 50% between scans or by more than 20% in two dimensions, it will need a biopsy.

Any lymph node involvement would mandate a biopsy straightaway.

Just a word of caution. These guidelines were designed for smokers and have not been validated in non-smokers. The predominant cancer in non-smokers is adenocarcinoma, which tend to be peripherally located ground glass nodules. Small cell cancers are solid nodules, also peripherally located, while squamous cell cancers are usually central lesions.

Endocarditis Is Not Always Infective

A 31 year old lady presents to you with a history of recent recurrent "bruising". Although she has no active lesions at the moment and looks quite well, pictures taken on her mobile phone show a substantial dark area on the left ring finger and larger, incomplete dark circular lesions on her upper shins. The GP has checked her ANA. It's negative. Inflammatory parameters are normal. She has two healthy children.

A 71 year old man presents with transient dark lesions on his fingers. On his second visit, you are lucky enough to catch sight of some of these dark areas on the fingers. They are tender. The patient is well and apyrexial without audible murmurs. You diagnose Osler's nodes and ask for blood cultures and echo.

All perfectly reasonable. Except that it may not be enough.

The prospect of embolic lesions from the heart valves is terrifying, but not all such cases are infective endocarditis. There are other possibilities.

Young women with SLE often have Libman Sacks lesions on left sided heart valves, particularly the mitral valve. This is three times more common in those with anti-phospholipid antibodies, which can exist independently of lupus. Although subjects with SLE and Libman Sack's lesions tend to have active lupus, often associated with lupus nephritis, subjects with aPL alone may have been hitherto asymptomatic. While it is important to dip the urine for blood and protein to screen for lupus nephritis, immune glomerulonephritis in infective endocarditis can cause an active urinary sediment.

In fact, Glomerulonephritis is one of the four immune manifestations of infective endocarditis, the other three being Osler's nodes, Roth spots and a false positive Rheumtoid factor (aid memoire GORR).

Treatment would be immunosuppression and anticoagulation, although there are no RCTs that support the use of the former in Libman Sacks endocarditis.

The old man with "Osler nodes" may have cancer, with thrombotic, non infective endocarditis. Clots, present on the heart valves (again more common on the left), are thought to be due to hypercoagulability. Such patients may often have occult DVTs or pulmonary emboli. Gastric or pancreatic cancers may have associated portal or mesenteric vein thrombosis. Apart from treatment of the underlying cancer, these patients need clexane. Warfarin would be ineffective.

Cancer and infective endocarditis can co-exist due to Streptococcus bovis septicaemia. These patients often have underlying colon cancer. Others have cirrhosis.

Subjects with left atrial myxoma can present exactly like subacute bacterial endocarditis with fever, lassitude, murmurs and embolic phenomena. Echo may pick up pedunculated lesions on the mitral valve.

A final non-infective cause of cardiac emboli is eosinophilia. Regardless of the underlying cause of eosinophilia, prolonged or high eosinophil counts go through three phases- cardiac microabscesses, a flabby, poorly contractile myocardium and endomyocardial fibrosis. It is in the second stage that clots build up, often in the left ventricle, which can then embolise and cause strokes, renal or splenic infarcts, just like infective endocarditis.

Eosinophilia can also occur secondarily in subjects with cholesterol emboli, usually from the aorta. These often present in the elderly with renal impairment and livedo in the lower limbs following an invasive procedure such as cardiac catheterisation. There are reports of cholesterol emboli occurring after anticoagulation.

It is important to consider these non-infective causes of endocarditis in subjects with cardiac vegetations on echo, who are culture negative and do not have the expected response to antibiotics.

Shoshin Beriberi: An Underappreciated Cause of Severe Heart Failure

Severe heart failure, often with cardio-renal syndrome, is a despairing condition to treat. Rescue therapies such as LVAD are not widely available and cardiac transplantation is rarely used, even in developed countries. Subjects may be on optimum medical treatment and may have already been fitted with CRT-D in cases associated with LBBB.

Certain hidden aetiologies deserve mention.

Correcting iron deficiency, through IV iron infusion, can help.

Alcoholics deserve special mention. Heart failure in alcoholics is often confused with anasarca caused by cirrhosis. Many of these subjects have alcoholic cardiomyopathy, and in refractory, newly diagnosed heart failure, a history of alcohol abuse must always be sought.

Beri-beri is now considered very infrequently. First described in Japan in subjects consuming polished rice, cases seen in the West mainly comprise alcoholics. However, severe thiamine deficiency occurs quickly in subjects with persistent vomiting, after bariatric surgery, after parenteral nutrition, and in cancer patients or other subjects with poor nutrition. Refeeding increases thiamine requirements, as does dextrose infusion.

Dry beri-beri is due to peripheral neuropathy, usually presenting with burning pain the feet and a glove and stocking distribution of patchy sensory loss. Wet beri-beri in its classic form is considered to be a phenotype of hyperdynamic, mainly right sided failure associated with peripheral vasodilatation. The left heart is largely spared.

However, there is another form of beriberi, called "Shoshin beriberi" which may not be widely known. ("Sho" means acute in Japanese, while "shin" denotes heart). This can cause acute bi-ventricular heart failure and if untreated, can be fatal within hours in advanced cases. In the two cases described by Wolf and Levin in The New England Journal of Medicine in 1960, subjects had striking peripheral cyanosis affecting the extremeties, tachycardia, cardiomegaly, hypotension, and pulmonary oedema. Both were alcoholics and one hadn't eaten for six days, subsisting on wine. There was striking improvement with IV thiamine in one patient, while the other case was only diagnosed at autopsy.

Another under-appreciated sign of thiamine deficiency in such subjects is lactic acidosis. This acidosis often drives severe tachypnoea and thus such subjects may have a paradoxically normal oxygen saturation, despite striking peripheral cyanosis. Thus, an alcoholic or otherwise malnourished subject presenting in acute pulmonary oedema, associated with anxiety, restlessness, dyspnoea and often central chest discomfort, with lactic acidosis on venous blood gas often upto 6-7 mmol/l, should be considered to have Shoshin beriberi. Intravenous thiamine may be lifesaving in such cases, and should be administered without delay even if a history of alcohol abuse is not immediately forthcoming. Whole blood thiamine or erythrocyte transketolase levels should be sent off concurrently.

It is well recognised that loop diuretics cause increased loss of thiamine in the urine. However, there is disagreement on whether this has the potential to worsen heart failure.

For some reason, Wernicke's encephalopathy and beri-beri do not co-exist very often. These disparate signs of severe thiamine deficiency are therefore rarely seen together.

The Striking Gender Bias of Hepatic Lesions

For unfathomable reasons, most hepatic lesions have striking gender bias.

Amoebic liver abscess is 9 times more common in men, and almost always present in the right lobe of the liver. It is almost always single. Coexistent amoebic colitis is rare and occurs in only 10% of cases. Serology is an excellent test.

Pyogenic abscesses are usually multiple. No gender bias.

Hepatocellular carcinoma occurs in a shrunken, cirrhotic liver, usually in the right lobe. It is 3 times more common in men, occurs in older subjects (usually >60) and is associated with a rise in serum alpha-fetoprotein in 70% cases.

Metastatic liver cancers are 30-times more common than primary hepatocellular cancer.

Fibrolamellar hepatocellular carcinoma occurs in much younger subjects- mean age 25. It accounts for 10% of primary liver cancers, and is not associated with a rise in alpha-fetoprotein. Distribution is equal between men and women, and between right and left lobes of liver. Prognosis is good, and if resected before metastasising , this cancer is associated with more than 60% 5-year survival. It occurs in a normal appearing liver (not cirrhotic) and has a central scar. Lesions are usually >10 cm, and can present with subcostal pain, intermittent pyrexia and weight loss over years.

Also with a central scar is focal nodular hyperplasia. It is usually solitary, discovered incidentally, is <5 cm in size, much more common in females and occurs in 3rd to 5th decades of life. Hepatic adenomas are almost exclusively seen in young women on oral contraceptives. When they occur in men, a history of anabolic steroid abuse must be sought. Cholangiocarcinomas are only slightly more common in men, but much more so when associated with sclerosing cholangitis, which is 9-times more common in men. Cholangiocarcinomas are often associated with a rise in serum Ca-19-9. However, this antigen is only present in subjects who have the Duffy blood group antigen. Gallbladder cancer is 2-6 times more common in women. Choledochal cysts are 3-4 times more common in women.

Random X Chromosome Inactivation as a Marker of Clonality

A female subject inherits two X-chromosomes, one from each parent. Shortly after conception, each somatic cell randomly inactivates (turns off) one of the X chromosomes. All daughter cells arising subsequently will therefore carry the same pair of inactive and active X chromosome. Since the process is random, the likelihood is that there will be a roughly equal split between inactivation of the paternal or maternal X chromosome.

The process by which this inactivation occurs is by methylation of the genes present on the inactivated X chromosome. Methylation silences the gene, an example of epigenetic modification.

The phenomenon of random X-inactivation can be used to determine the clonality of haematopoetic cells, when these cells are suspected to be neoplastic.

Determining clonality is easy for B cells and T cells. Each B cell experiences an isotype switch from IgM to IgG, IgA, or IgE during its development. B cells then rearrange their immunoglobulin heavy chains and express only the kappa or lambda light chain. Thus a lymphoma arising from a B cell clone will carry a rearranged mu, gamma, alpha or epsilon heavy chain and either kappa or lambda light chain.

T cells don't express cell surface immunoglobulins, but do carry T cell receptors. Just like B cells, they rearrange these receptors upon exposure to their cognate antigen. T cells carry alpha/beta and gamma/delta receptors, although only one of these pairs is expressed. It is easier to test for rearrangement of gamma receptors, because they have less polymorphisms.

However, such unique receptors or cell surface immunoglobulins do not exist for other haematopoetic cells, such as natural killer cells, macrophages or eosinophils. (Yes, they do express generic receptors, but these are not unique for each cell, unlike in T or B cells, which have to recognise specific antigens)

In females, as long there is heterozygosity, inactivation of a gene present on the X chromosome can be used to determine clonality in these haematopoetic cells. Such genes include phosphoglycerate kinase (PGK), hypoxanthine guanine phosphoribosyl transferase and human androgen receptor. Such analysis cannot be done if a both alleles of the gene are the same, i.e. with a state of homozygosity.

PGK has been used, but carries the drawback that there is only 40% heterozygosity in the population for this gene. Most such analyses are now done with the Human Androgen Receptor gene (HUMARA), as the prevalence of heterozygosity is very high- around 90%.

Restriction endonucleases which are methylation sensitive, are used to digest the DNA on each allele. The methylated (inactivated) allele will not be broken down, while the unmethylated (active) allele will be. All daughter cells arising from a single (clonal) cell will carry either the unmethylated (cleaved) or methylated (uncleaved) DNA, but not both. In homozygotes, since the paternally and maternally inherited alleles would be identical, it would not be possible to tell whether the paternal or maternal allele of the gene was present in the cells under consideration.

Males carry only one X-chromosome, hence the phenomenon of random X inactivation cannot be used to determine clonality in men.

Natural Killer Cell Alloreactivity in Haplo-identical Stem Cell Transplantation

Only 30% of subjects needing haematopoetic stem cell transplantation (HSCT) will find HLA identical donors. In the case of related donors, the requirement is to match all 6 alleles at HLA A, B and DRB1, while, for unrelated donors, matching needs to be 8/8, i.e. at HLA A, B, C and DRB1.

An alternative to fully matched donors, is using a haplo-identical donor. This could be a parent, an offspring, a sibling or half-sibling. It is estimated that there is a mean of 2.7 haplo-identical donors available for every subject needing HSCT. These donors are naturally highly motivated, being related donors. Unlike cord blood donations, haplo-identical donors will be available for further infusions of stem cells or lymphocytes at a later date for graft failure or infections respectively if needed.

However, samples of bone marrow or peripheral blood obtained from haplo-identical donors have large numbers of T-cells, giving a much higher risk of GVHD. There is severe bidirectional alloreactivity, also increasing the risk of graft failure. This can be mitigated by depleting the T-lymphocytes in the donor sample with pre-treatment with anti-thymocyte globulin and drugs such as cyclophosphamide or busulfan, and by reducing the risk of GVHD with medthotrexate and cyclosporin or tacrolimus.

Children tend to do better when they receive a haplo-identical graft from the mother rather than the father. Similarly, when receiving the graft from a sibling, they do better if the haplotype mismatch applies to the maternal antigens rather than paternal ones. This is due to the effect of non-inherited maternal antigens (NIMA). It is thought that exposure to maternal antigens in utero, even if those antigens have not been inherited, tolerizes the child's immune system to NIMA. The same does not apply to paternal antigens. Mismatch for paternal antigens carries a worse outcome.

In 2002, Ruggeri and colleagues from Perugia, Italy published a seminal work of research in Science that was to unleash a decade long quest to investigate the role of Natural Killer Cells (NK cells) in transplantation. The role of NK cells, as a part of innate immunity, is to find and destroy cancer cells and infected cells before the adaptive immune system is called into play. They do this by recognising the absence of cognate HLA Class I receptors on the surface of their target cells. If such receptors are detected, the NK cells do not kill them, while if the "self" receptors are absent or not recognised, cytolysis occurs.

To this end, NK cells carry two types of receptors, the NKG2D/CD94 hetero-dimeric receptor which is inhibitory, and a much larger group of receptors called Killer Cell Immunoglobulin-like receptor (KIR), which is comprised of some 15 genes. KIR receptors are broadly of 2 types- A & B. Type A KIR receptors do not have a great deal of antigenic heterogeneity, and are mostly inhibitory. Type B KIR receptors are much more diverse and include both inhibitory and activating receptors. The inhibitory receptors have the suffix L (e.g. KIR2DL. KIR3DL) while activating receptors end with a S (e.g. KIR2DS).

After HSCT, NK cells are usually the first to be repopulated, before T-cells have had time to recover. It is probably stating the obvious to mention that T-cells account for the bulk of graft versus leukaemia (GVL) effect, but increase the risk of GVHD.

Ruggeri and his colleagues found that in T-cell depleted stem cell transplants, when there was mismatch between the recepient's and donor's KIR ligands (the receptors for KIR), GVL effect was better, leukaemia free progression (LFP) was longer and GVHD occurred less often. It is easy to understand why NK cells would attack leukemia cells, but how do you explain a reduced incidence of acute GVHD? It is thought that NK cells do this through allo-reactivity against the recipient's antigen presenting cells (mismatched for KIR ligands).

This effect was not replicated in T-cell replete grafts, presumably because T-cells would increase the risk of GVHD and thus nullify the effect of NK cells.

It is now clear that it is not just the host characteristics that influence graft survival. Unrelated donors who have at least one KIR-B haplotype (KIR B/x, as opposed to KIR A/A), display greater GVL effect, even in T-cell replete grafts. There may therefore be a case or deliberately selecting donors whose NK cells carry KIR-B. KIR-B alleles lying in the centromeric rather than telomeric position appear to provide greater GVL effect. There is also a dose response effect, with greater number of KIR B alleles providing more efficacy.

Further, recipients who are homozygous for HLA-C2 benefit less than those heterozygous or homozygous for HLA-C1. It appears that the activating receptor KIR2DS1, whose cognate receptor is the HLA Class C molecule, will only destroy leukaemia cells that carry HLA-C1, but is tolerized by HLA-C2. Fortunately only 15% of subjects with acute leukaemia are homozygous for HLA-C2.

Finally, mismatch for HLA-Class C antigen between donor and recipient increases the benefits offered by NK cells in terms of GVL effect and LFP through alloreactivity.

It is worth mentioning that these salutary effects of NK cells in haplo-identical and unrelated-donor HSCT are only seen for recipients with AML, but not with ALL.

Hence, if multiple haplo-identical or unrelated, otherwise matched donors are under consideration for a recipient with AML, it is worth selecting the donor with KIR B alleles over a donor who is homozygous for KIR A. There is less agreement over whether to select donors who are deliberately mismatched for KIR ligands to increase NK cell alloreactivity in haploidentical transplants, as some studies have shown a higher risk of GVHD.

References:

1. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

2. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SG, Geraghty D, Spellman S, Haagenson MD, Ladner M,Trachtenberg E, Parham P, Miller JS: Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010; 116: 2411–2419.

Differentiating Neuropsychiatric Lupus from Anti-Phospholipid syndrome

We've all been there. An elderly woman with obvious cognitive dysfunction, otherwise well and apyrexial, but with high ESR/CRP, is screened for "autoimmunity". The screen comes back as strongly positive. The patient is positive for ANA, dsDNA, C3, C4, lupus anticoagulant and IgG antibodies to beta-2 glycoprotein I. A question is asked. Does this patient have "cerebral lupus?" Do we give steroids, anticoagulation, or both?

Even experts find it difficult to make such determinations. There is too much soft research, nonspecific tests and grey areas passed off as "evidence" in the literature that confuses rather than resolves the issue. However, there are some hard facts that can be relied on. One must take care to ask the right questions.

1. Lupus vasculitis as a cause of neuro-psychiatric lupus (NP lupus) is uncommon~3% of all cases of NP lupus. Most patients with lupus vasculitis present with fever, severe headache and confusion and may progress to coma. A true emergency. The focus is on ruling out infection and TTP, and immunosuppressing ASAP with high dose steroids and cyclophosphamide.

2. Most cases of dementia related to lupus have stable, non-progressive disease and do not need to be immunosuppressed. Aspirin and statins are the order of the day.

3. Two-thirds of neuro-psychatric manifestations in lupus are due to non-lupus causes. Consider infections, medications (e.g. aseptic meningitis caused by NSAIDs and azathioprine, CVA caused by steroids), posterior reversible encephalopathy syndrome in those with very high BP and visual disturbances, TTP, atherosclerosis (risk factors diabetes, BP, hyperlipidaemia and smoking- all treatable causes), obstructive sleep apnoea (causing headache and fatigue).

4. Lumbar puncture is one of the most useful tests in NP lupus. Neutrophilia and high CSF protein indicates vasculitis (if bacterial meningitis can be ruled out). Anti-phospholipid (APL) syndrome is associated with raised protein but no pleocytosis. Presence of raised protein and mild lymphocytic pleocytosis indicates non-vasculitic active NP lupus (raised protein more common than pleocytosis). Hypoglycorrhachia indicates infection, with the exception of transverse myelitis, where CSF sugar is often low.

5. CSF IgG levels, IgG index, and CSF oligoclonal bands are really useful tests. CSF IgG levels are raised in over 2/3 of patients with NP lupus and a CSF IgG level> 6mg/dl is virtually pathognomonic of active NP lupus, although present in only 40% of cases. A raised CSF IgG index and CSF oligoclonal bands are seen in ~80% of cases with active NP lupus, particularly those with diffuse manifestations such as encephalopathy and psychosis. IgG index and oligoclonal bands will be normal/absent in those with focal symptoms such as hemiparesis caused by APL syndrome or chorea. CSF Q-albumin is not an useful test as it'd be raised in any aetiology that causes breakdown of the blood brain barrier such as stroke.

(IgG index is the ratio of two ratios- CSF IgG/CSF albumin divided by serum IgG/serum albumin. Normal IgG index is less than 0.66)

(Q-albumin is simply the ratio between CSF albumin and serum albumin).

6. Demographics are really important. Lupus patients with chorea and transverse myelitis tend to be young women. Always check ANA in a young woman who develops chorea. A positive ANA makes it more likely than not that she has lupus. APL is overrepresented in these two conditions, and in those with seizures.

7. Always check NMO-IgG in a lupus or Sjogren's patient who develops optic neuritis or transverse myelitis. The antibody is present in 75% of subjects with neuromyelitis optica, and carries an adverse prognosis, with multiple recurrences. Anti-Ro antibodies are often associated.

8. Large vessel stroke in SLE is bad news. Can be caused by APL, hypertension or TTP, the typical patient is 35 years old, 86% have active SLE at the time of stroke, and 40% will die in the short term. Thirteen percent will have recurrent stroke.

9. Recurrent TIAs with small infarcts is more characteristic of APL.

10. MRI is overrated. Although it is the preferred imaging procedure in picking up lesions of NP lupus, these typically appear as small white matter lesions on T2 weighted MRI. These are non-specific and can be found in many subjects with lupus who do not have NP manifestations.

11. Studies on anti-neuronal antibodies, antibodies to NMDAR and anti-ribosomal P antibodies are simply too discordant for these tests to be useful, although the latter is reasonably specific for lupus with severe psychosis or depression.

12. The old adage about ESR and CRP in SLE is true. ESR tends to be raised in subjects with lupus, while CRP rises with infection or vasculitis. A subject with NP lupus with raised CRP should be suspected to have infection or vasculitis.

13. NP lupus typically occurs in subjects with active lupus, but less commonly, can be the first presentation of the condition.

14. Scan the heart in all patients with NP lupus. Non infective vegetations (Libman sacks endocarditis) on left sided valves can be a source of emboli for subjects with stroke or multi-infarct phenotypes. APL is overrepresented in such subjects.

15. Don't ignore investigations you'd otherwise perform in non-lupus subjects with stroke, young or otherwise. Thus, carotid dopplers in all patients, and serum homocysteine in young patients should be checked. Young patients with recurrent stroke should be screened for patent foramen ovale through bubble contrast echo.

16. Presence of livedo reticularis (Sneddon's syndrome), thrombocytopenia, adverse obstetric history, or a history of clots makes it more likely that APL is the cause. Subjects with arterial clots related to APL tend to have recurrent arterial clots, while those with venous clots tend to have recurrent VTE, albeit at different sites.

Drug Side Effects can be Predictors of Better Outcomes in Oncology

Drug side effects can limit the usefulness of even the most powerful drugs in medicine. However, there are certain situations in Oncology where the occurrence of certain drug side effects predicts better outcomes for the patient...eventually, if the side effect is recognised and treated.

An example of this can be found in the treatment of metastatic colorectal carcinoma with monoclonal antobodies to EGFR receptors, namely cetuximab and panatumimab. These two agents commonly cause a generalised papulopustular rash resembling acne. However, the rash doesn't occur in all patients, and when it does occur, can be of varying severity. Subjects who develop the rash, or those who have a more severe form of the rash, are likely to have longer progression free survival from cancer.

There is one caveat however. The rash only predicts longer survival in subjects who do not have mutations in the KRAS oncogene, i.e. have wild type KRAS. In subjects with mutated KRAS, the acneiform rash caused by monoclonal antibodies to EGFR does not portend a better outcome. Therefore, in subjects with wild type KRAS, increasing the dose of cetuximab or panitumumab to the point that the rash appears can be a powerful strategy to improve progression free survival.

Another example of this slightly non-intuitive phenomenon of a serious side effect being the harbinger of an eventually better outcome can be observed in patients with malignant melanoma treated with the ipilimumab. Ipilimumab is a monoclonal antibody to CTLA-4 (also called CD152), a receptor found on activated T-cells. CTLA-4 is a "negative" receptor. When stimulated by its ligands, namely B7-1 (also called CD80) or B7-2 (also called CD86) it inhibits the function of the activated T cell. Thus CTLA-4 exists to provide a counterbalance to CD28, the "positive" receptor on T cells, stimulated by the very same ligands that bind to CTLA-4, and thus stop the T cells from running amok.

By inhibiting the inhibitory receptor CTLA-4, ipilimumab therefore stimulates the T cells to seek out and destroy the cancer cells. This strategy works spectacularly well for melanoma, but unfortunately not so well for most other tumours. However, activated T-cells are like a loaded gun. They will attack cancerous cells, but might also harm innocent bystanders and thus cause colitis, dermatitis, hepatitis, neuropathies, or endocrinopathies, such as hypophysitis.

Hypophysitis can be troublesome, particularly by affecting the adrenocortical and thyroid axes. Severe fatigue and headache culminating in life threatening adrenocortical insufficiency may occur in approximately 1.5% of treated patients. However, this autoimmune side effect is now well recognised and can be managed effectively with replacement doses of hydrocortisone (and thyroxine and sex hormones, where applicable, although these other anterior pituitary hormone deficiencies tend to be self limited). Paradoxically, the development of hypophysitis predicts improved survival following ipilimumab therapy. Nowhere is the old adage, "if it doesn't kill you, it makes you stronger" better epitomised than with these agents used by oncologists.

An Approach to Penicillin Allergy

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

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

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

Gel-Coombs Classification

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

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

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

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

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

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

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

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

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


Reference:

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

Fractional Excretion of Nitric Oxide in Assessment of Inflammatory Asthma

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

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

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

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

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

References:

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

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

Dealing With Low Flow, Low Gradient Aortic Stenosis

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

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

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

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

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

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

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

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

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

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

Pressure = Flow*Resistance

or Resistance = Pressure/Flow

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

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

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

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

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

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

An Approach to Myopathy in the Rheumatology Clinic

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

History

The three questions to ask to rule out metabolic myopathies

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

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

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

The four questions to rule out IIM

Raynaud?
Supports anti-synthetase syndromes.

Dysphagia?
IIM or overlap with scleroderma.

Joint pains?
Favours anti-synthetase syndromes

Weight loss?
Favours malignancy

Severe pain?
Makes IIM unlikely

Six questions to rule out toxin/drug induced myopathy

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

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

Are you on statins or fibrates?

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

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

Do you take nutritional supplements?
Creatine

Four questions to rule out adult onset muscular dystrophies/myopathies

Family history

Diabetes+ Hypogonadism+Cataracts
Myotonic dystrophy.

Diabetes+Deafness
Mitochondrial myopathy

Four questions to rule out MND (CK<1000)

Fasciculations?
Cramps?
Weight loss?
Nasal regurgitation?

One question to rule out parasitic muscle disease

Do you eat uncooked pork?
Trichinellosis

Examination

PM & DM causes symmetrical & proximal myopathy

IBM causes weakness of wrist and finger flexors- often asymmetrical

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

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

Short stature? Ptosis and squint but no diplopia
Mitochondrial myopathy

Fasciculations, Babinski
MND

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

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

Synovitis?
Anti-synthetase or overlap

Periorbital oedema?
DM, PM or Trichinellosis,

Investigations

Metabolic myopathy

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

Mitochondrial myopathy

Fasting lactate

Myotonic dystrophy

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

Trichinellosis

Eosinophilia

Serology- ELISA, followed by Western Blot

Drug/Toxin induced Myopathy

Screen for drugs of abuse

EMG , Muscle biopsy & MRI

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

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

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

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

EMG will pick up myotonic dystrophy.

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