May 25, 2014

14 lessons from HIV Update 2014

HIV update 2014 was held in Seremban on 22nd May 2014. 

1. As of 2011, there were approximately 34 million people living with HIV infection in the world.
2. In 2011, the incidence of new HIV cases in Malaysia was 12.2 per 100000 people. The state of Johor had reported the greatest number of new cases that year. 

3. Antiretroviral therapy should be started according to the CD4 cell count or when there is “double trouble” (HIV infection plus another condition). If we decide to start antiretroviral therapy based on the CD4 count, then for practical purposes, in Malaysia, we start when the CD4 count is below 350 cells per cubic mm. The ideal is probably to start when the count is below 500 cells per cubic mm. Conditions that constitute double trouble include: HIV plus active tuberculosis infection; HIV plus HBV infection; when an HIV patient has a sexual partner who is not positive; when a woman with HIV is pregnant or breastfeeding; when the patient with HIV is a child below 5 years of age.

4. A template for initiating antiretroviral therapy is: Efavirenz plus Tenofovir plus Lamivudine or Efavirenz plus Tenofovir plus Emtricitabine. Other combinations involving the cheaper drug zidovudine are also possible. An important update is that Efavirenz is no longer considered teratogenic now. Important points to remember are: Efavirenz causes CNS toxicity and skin rashes.

5. The HIV viral load (HIV RNA count) is more important for decision making than the CD4 count. This is because the CD4 count is subject to variations caused by factors other than HIV infection.

6. The gold standard for the diagnosis of HIV used to be the ELISA test (for detection of antibodies) and the Western Blot test (for detection of antigens).  Nowadays different methods (rapid assay tests) are used to detect antibodies and antigens.

7. One quarter of new deaths from HIV infection are due to tuberculosis in the world. The WHO recommendation is to give co-trimoxazole (Bactrim) for all patients who have both tuberculosis and advanced HIV infection because co-trimoxazole protects against infections that such people with advanced immunosuppression are also susceptible to. The drug should be given for at least six months.
8. Diagnosing tuberculosis can be difficult when resources to do so are not easily available. A useful aphorism to remember is: If patients do not have all these 4 symptoms of cough, fever, night sweats and loss of weight, they are unlikely to have tuberculosis. Conversely if they have one or more of these symptoms, the diagnosis of tuberculosis should be suspected and options to confirm or rule out the diagnosis should be explored.

9. It has been found that 57 percent of all people being treated for tuberculosis develop hepatitis. In this regard, pyrazinamide and isoniazid are more likely than rifampicin to be the cause of the hepatitis. Ethambutol and Streptomycin are very unlikely to cause hepatitis.

10. When Efavirenz is used along with Ethambutol, the serum levels of Efavirenz will decrease.
11. Efavirenz should be avoided in people prone to depression.
12. When a patient on antiretroviral therapy develops proteinuria or acute kidney injury, suspect Tenofovir induced damage to the proximal convoluted tubules of the kidney.
13. When a patient on antiretroviral therapy develops anemia, suspect zidovudine as a cause.


14. Failure of antiretroviral therapy can be defined thus: Virological failure is said to be present when the viral load is more than 1000 copies per millilitre on 2 occasions, more than 3 months apart. Immunological failure is said to be present when the CD4 count remains less than the baseline (before treatment) or remains less than 100 cells per millilitre persistently. Clinical failure is said to be present when a new illness due to immunosuppression occurs after 6 months of treatment. 

May 8, 2014

Using rubrics for decision making

Daniel Kahneman, the Nobel Prize winning Professor of Psychology from Princeton University, has written a book titled “Thinking, fast and slow”. In this book there is a chapter called “Intuitions versus Formulas”.  He explains that our evaluation of complex problems can sometimes be standardised by the use of algorithms or formulas with numerical values attached to them.  There are two examples that I wish to quote from that book because I feel it is relevant to how we can use rubrics (or formulas with scores) for standardising the evaluation of student portfolios.

1. How do you evaluate the stability of a marriage?
The formula (frequency of lovemaking – frequency of quarrels) will give a fair idea of marital stability. If the answer is not a negative number, the marriage is probably stable. 

2. How do you evaluate the chances of survival in a new born child?
Obstetricians have always known that infants who do not breathe well within a few minutes of birth are at high risk of brain damage or death. But until the anaesthetist Virginia Apgar wrote a simple algorithm incorporating five variables to observe in all new born infants, with a score assigned to each variable, doctors and midwives used their clinical judgement to determine whether babies were in distress. Some watched for breathing problems while others focused on how soon the baby cried. Without a standardised procedure, danger signs were often missed and many new born infants died. The Apgar scoring system gave everyone a consistent standard for determining risk and helped everyone evaluate this risk in the same way as experienced obstetricians. The Apgar test is credited with helping to reduce infant mortality.

Feb 13, 2014

A patient with hypernatremia

A 75 year old man with a history of chronic alcohol abuse presented with bleeding per rectum. He was diagnosed to have bleeding haemorrhoids and was admitted in the hospital and given intravenous fluids. A day later he became confused and agitated. He was suspected to have delirium tremens and was treated with parenteral Thiamine. His agitated behaviour subsided but he became drowsy and lethargic. At this point his serum sodium was noted to be 168mmol/L. His blood urea was elevated but his serum creatinine was within normal limits.

About hypernatremia
Hypernatremia should be considered a water-problem and not a salt-problem. People develop hypernatremia only when there is an impairment of the thirst mechanism or when there is limited access to water. This elderly man developed hypernatremia in the hospital in the setting of an alcohol-related change in behaviour and sensorium. We can assume that his hypernatremia reflects impaired release of vasopressin from the brain (diabetes insipidus) along with insufficient fluid intake. There is evidence that alcohol can damage the supraoptic and paraventricular nuclei in the brain. (Reference) 

The diagnosis of diabetes insipidus is suspected when a person has polyuria (more than 3 litres of urine in a day) with hypotonic urine (urine osmolality less than 300mOsm/kg). As a general rule, in all patients who have polyuria with hypotonic urine, we must suspect three possibilities: compulsive polydipsia, central diabetes insipidus and nephrogenic diabetes insipidus. The fluid deprivation test can help us confirm or rule out compulsive polydipsia. The desmopressin stimulation test will help us identify nephrogenic diabetes insipidus. 

Treating hypernatremia
Hypernatremia is dangerous because it dehydrates brain cells and damages them. Before treating hypernatremia, we should know the duration of hypernatremia. If the condition has been present for less than 24 hours, rapid correction is safe. In this patient we have to assume that the hypernatremia was present for more than 24 hours. Hence his hypernatremia should be corrected slowly. Rapid correction can lead to cerebral edema. Slow correction means reducing the sodium levels by not more than 10 to 12 mmol/L per day.

Correcting elevated serum sodium
In correcting hypernatremia we use 5 percent dextrose which does not contain any sodium at all. To know how much the serum sodium will fall by giving 1 litre of 5 percent dextrose, there is a formula:

(Amount of sodium in the infusate minus the serum sodium) divided by (total body water plus 1) is equal to the amount by which the serum sodium will fall. 

His total body water = 50 percent of body weight = 30 litres because his body weight was estimated to be 60kg.
The calculated fall in serum sodium by infusing one litre of 5 percent dextrose will be: (0 – 168) divided by (30+1) = 5.4mmol/L

A fall of 10mmol/L in serum sodium needs: 10 divided by 5.4 = 1.85 litres of 5 percent dextrose.

Now we must add in the insensible and obligatory losses of fluid from the body per day. This depends on factors like urine output, body temperature, ambient temperature and respiratory rate. As an approximation, if his urine output is 900 ml per day, and insensible losses are 600ml per day, we have to add (900+600) = 1.5 L to the daily fluid requirement.

Hence he should be given (1.85 + 1.5) = 3.15 L of 5 percent dextrose per day in order to reduce serum sodium by 10mmol/day. 

This means infusing the fluid at the rate of approximately 130ml per hour. This is a rough guide only. We must check the serum sodium every 1 to 2 hours and adjust our infusion rate accordingly. At all costs, we must avoid a rapid fall in serum sodium.

What predisposed this patient to develop a confusional state in hospital?
There are two possibilities. Delirium tremens and acute onset of beriberi.
Delirium tremens is a severe clinical manifestation of alcohol withdrawal and shows itself as a confusional state with features of sympathetic over-activity. It generally occurs 3 to 10 days after stopping alcohol intake. It is important to treat it urgently because cardiovascular collapse can occur. Benzodiazepines in adequate doses should always be used. Beta blockers can be added if necessary. Attention must be paid to fluid and electrolyte balance and management of other medical / surgical conditions in the patient.
Beriberi can present as a confusional state – Wernicke’s encephalopathy and Korsakoff psychosis. People who chronically abuse alcohol may have low levels of Vitamin B1 or thiamine in their bodies. When such people are given dextrose containing fluids, they can develop acute thiamine deficiency because whatever little thiamine is present in them is used up for the metabolism of glucose.

 How should diabetes insipidus be treated?
If this patient is confirmed to have central diabetes insipidus, he will need replacement doses of vasopressin. Vasopressin (trade name Pitressin) can be given intramuscularly or subcutaneously twice or thrice a day. There is also a form of vasopressin that can be given as a nasal spray or as a tablet.

References:


Jan 28, 2014

Prescribing statins - current concepts

What is the dose of statin that should be prescribed to patients who have clinically evident coronary artery disease?
When a patient below the age of 75 years has evidence of coronary artery disease, statins in appropriately high doses should be prescribed irrespective of their serum cholesterol values. A high dose (or intensive dose) for Atorvastatin refers to 40 to 80mg per day; a similar dose for Simvastatin is 40mg per day.

Is the dose of statin prescribed to a patient determined by the LDL - cholesterol value?
The new 2013 cholesterol lowering guidelines tell us that the decision to start a statin can be determined, in part, by the LDL cholesterol level. But the dose (high intensity versus moderate intensity) is determined by parameters other than the LDL cholesterol value. 

When should serum creatine kinase (CK) be tested when patients are on statins?
CK needs to be tested only when patients on statins complain of muscle pain or muscle weakness.

How can muscle pain due to statins be differentiated from other causes of myalgia?
Myalgia due to statins will resolve within 2 weeks of stopping the drug. When muscle pain persists beyond 2 weeks after discontinuing statins, other causes of myalgia must be considered.

Should liver function tests be done routinely when patients are on statins?
No. It is not necessary.

Should all patients with diabetes be prescribed with a statin?
All diabetic patients between the ages of 40 and 75 years should generally receive a statin unless their LDL cholesterol level is unusually low (below 1.8mmol/L). Whether low dose (moderate intensity) or high dose (high intensity) statins are needed should be decided by their 10-year risk of developing atherosclerotic coronary artery disease.

Is there any role for the combination of a statin with a non-statin (fenofibrate / gemfibrosil / nicotinic acid)?
Yes. There is definite evidence for doing so in patients with familial hypercholesterolemia because the reduction in cardiovascular risk is proportional to the degree of lowering of LDL cholesterol. The diagnosis of familial hypercholesterolemia should be suspected in patients with LDL cholesterol levels more than 4.9mmol/L (190mg/dL). Whether there is a benefit in combining a statin with a non-statin for those with diabetes and coronary artery disease is still not clear. When a statin is combined with a fibrate, it is better to use fenofibrate (and not gemfibrosil) because it is safer.

Can statins be continued during pregnancy?
Statins and non-statin cholesterol lowering drugs are classified as pregnancy category X and should not be taken during pregnancy and while breast feeding. Those who are on statins should discontinue them 2 to 3 months before becoming pregnant. 

Is there an increased risk of new-onset diabetes due to statin therapy?
Yes, but the risk is modest. With low dose statin therapy, 1 out of 1000 will develop diabetes per year. With high dose statin therapy, 3 out of 1000 will develop diabetes per year according to available evidence. On the other hand, appropriately used statin therapy prevents 5 to 6 cases of atherosclerosis induced vascular disease per 1000 population per year. 

Is there any role for using statins for primary prevention in individuals who are younger than 40 years of age if they do not have diabetes or heart disease?
Yes, in selected individuals. Young people who have risk factors like: a strong family history of premature coronary artery disease, an LDL cholesterol more than 4.1mmol/L (160mg/dL), a high sensitivity CRP level more than 2mg/L, or a coronary calcium score more than 300units can be considered for statin therapy as primary prevention. Moderate intensity (lower dose) statins are recommended if their calculated lifetime risk of developing coronary artery disease is not high. High intensity statin therapy is recommended if the calculated lifetime risk is high.

How are the statins different from each other in their LDL- cholesterol lowering ability?
When statins are evaluated based on their ability to lower LDL cholesterol, we note that 5mg of Rosuvastatin is equal to 10mg of Atrovastatin is equal to 20mg of Simvastatin is equal to 40mg of Lovastatin. The relationship between dose of statin and degree of LDL-cholesterol lowering is not linear: doubling of a statin dose does not double the fall in LDL cholesterol, but only an extra 6 percent fall will be seen.



Based on the 2013 cholesterol lowering guidelines from the American Heart Association and the prevention guidelines clinical vignettes . 


Jan 2, 2014

Acute and chronic gout

The following is based on the Malaysian Clinical Practice Guidelines for Management of Gout (Published in October 2008)

1. The first line treatment for acute gouty arthritis is non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, diclofenac and indomethacin. Aspirin is not recommended because it increases uric acid levels in the blood unless given in very high doses.

Question: A patient with acute gouty arthritis has peptic ulcer disease and hence cannot be prescribed any of the traditional NSAIDs. What can be done for pain relief in this situation?
Answer: We can use either COX-2 (cyclooxygenase 2) inhibitors like Celecoxib or Etoricoxib. We can also use Colchicine. A third option for pain relief, particularly in elderly people and in those who have renal disease, is the use of glucocorticoids. Short courses of oral prednisolone are effective in providing pain relief. Intra-articular injections of corticosteroids are also helpful.


2. Long term therapy with Allopurinol to reduce serum uric acid levels should be initiated in those who have chronic gout – that is, those who have experienced 3 or more episodes of acute gouty arthritis in a year, those who have erosive gouty arthritis, those who have tophi, and those who have uric acid nephropathy or uric acid stones.

Question: How is Allopurinol prescribed?
Answer: Allopurinol should be started in a low dose of 100 to 150mg once a day. After 3 to 4 weeks, the dose can be increased to usual maximum dose of 300mg per day. In those who have renal impairment, the dose of Allopurinol should be appropriately reduced. For example, if a patient with gout has end stage renal failure, the dose of allopurinol should not exceed 100mg once in 2 to 3 days. If a patient with gout has Stage 3 CKD, the maximum dose should not exceed 200mg per day. The usual dose of 300mg per day should only be prescribed for those with normal renal function.

Question: Can Allopurinol be prescribed for those with asymptomatic hyperuricemia?
Answer: It is not necessary to prescribe Allopurinol for all asymptomatic people with elevated uric acid levels because most of them will never suffer from gout. However, if the uric acid level is very high (about twice the upper limit of normal), it is better to prescribe allopurinol to reduce the risk of developing nephropathy. Prophylactic use of allopurinol is also recommended when a rapid increase in serum uric acid  is anticipated – as in treatment of leukemias and lymphomas.

Question: Since allopurinol has the potential to cause severe allergic reactions and bone marrow depression, is there an alternative drug for reducing serum uric acid?
Answer: Probenecid is also a uric acid lowering drug. Unlike allopurinol, probenecid increases the excretion of uric acid in the urine. Hence probenecid is not recommended for those who have uric acid nephropathy or uric acid nephrolithiasis. Ideally, urinary excretion of uric acid should be measured and probenecid should be prescribed only for those who do not have elevated urinary uric acid levels. 

Question: Will allopurinol therapy increase the risk of acute gouty arthritis?
Answer: Yes, there is an increased risk of acute arthritis during the initial period after allopurinol is initiated. That is why one should not prescribe allopurinol during an acute episode. To minimise acute episodes while initiating allopurinol therapy, low doses of colchicine (0.5mg twice a day) can be given. Colchicine can be stopped when the patient has not suffered acute arthritis for 6 months or when serum uric acid levels are normal for one month.

Question: Should allopurinol be stopped when a person, who is already on allopurinol, develops acute gouty arthritis?
Answer: No. Allopurinol need not be stopped in this situation. 

Question: What is risk when Allopurinol is prescribed along with Ampicillin?
Answer: There is an increased risk of developing a skin rash due to allopurinol.

Question: What is the risk of prescribing allopurinol with warfarin?
Answer: There is the risk of bleeding because allopurinol reduces the metabolism of warfarin and increases its half-life.


3. Polyarticular gout mimics rheumatoid arthritis. Gouty arthritis can lead to osteoarthritis.

Question: How do the subcutaneous tophi in gout differ from the subcutaneous nodules of rheumatoid arthritis?
Answer: Tophi are painless while rheumatoid nodules are generally painful.

Question: Is it possible to differentiate gouty arthritis from osteoarthritis with an x-ray of a painful joint?
Answer: Yes. The joint space is preserved in acute gouty arthritis while the joint space is narrowed in osteoarthritis.


4. A normal serum uric acid in a person with acute arthritis does not exclude gout.

Question: Can a therapeutic response to colchicine be used to diagnose gout?
Answer: Yes. Acute gouty arthritis responds within 48 hours to colchicine.


5. Alcohol should be restricted or avoided in all patients with gout.

Question: Why is alcohol restriction necessary in gout?
Answer: Alcohol reduces the excretion of purines. Uric acid is the result of purine metabolism.


6. Drugs that increase uric acid levels can provoke acute gouty arthritis.

Question: A patient with diabetes, hypertension and ischemic heart disease experiences frequent gouty arthritis. Which of her medications may need to be changed?
Answer: Is she on thiazide diuretics for hypertension and low dose aspirin for heart disease? If yes, these should be changed.


7. Food that is high in purine content should be avoided by those who have gout.

Question: Should eggs be avoided by those who have gout?
Answer: No. Eggs have low purine content.

Question: Should mushrooms, beans and peas be avoided by those who have gout?
Answer: These foods have moderate purine content and should be eaten less frequently than usual.

Question: Can those with gout eat red meat, anchovies and sardines?
Answer: These are food items with high purine content and should be avoided.


Dec 19, 2013

Cyanosis without hypoxia

Clinically evident cyanosis is often due to increased levels of reduced hemoglobin in the blood caused by cardiac or pulmonary diseases. Recently a 23 year old woman presented with cyanosis of the tongue and finger tips. She was not anemic or icteric. She did not have any cardiac or pulmonary disease. Her capillary oxygen saturation was 93 percent. When a few drops of her blood (dark brown in colour) were spilled on a white filter paper, no change in colour was noted after adequate exposure to the atmosphere.

This provoked a discussion on the causes of cyanosis without hypoxia.

We discussed methaemoglobinemia as a possible cause. Methaemoglobinemia is a condition where the hemoglobin molecule has a ferric iron instead of the normal ferrous iron. This condition can occur following exposure to drugs like nitrites, sulphonamides and some chemical dyes. When iron is in the ferric state, hemoglobin does not easily release its oxygen to tissues. Methaemoglobinemia can also be due to inherited disorders: deficiency of the enzyme within red cells that normally converts iron from a ferric state to a ferrous state - an enzyme called methaemoglobin reductase - can result in methaemoglobinemia. Another reason is the presence of an abnormal hemoglobin called Hemoglobin M.

Our patient however did not have methaemoglobin reductase deficiency. Her hemoglobin electrophoresis showed the presence of the hemoglobin variant called Hemoglobin M. And that explained why she had cyanosis without hypoxia.

Nov 18, 2013

The Mantoux tuberculin skin test - interesting facts

The Mantoux test or the Tuberculin Skin Test (TST) is one of those tests that most doctors will do when faced with a patient who is suspected of having tuberculosis. The test involves the intradermal injection of 0.1ml of a protein called tuberculin purified protein derivative. The test is interpreted as positive or negative according to the size of induration on the skin (not erythema), measured perpendicular to the long axis of injection, between 48 and 72 hours after the injection.

The TST is not a very sensitive test. In those who are not suffering from any kind of disease that compromises their immunity, the test has a sensitivity of about 95 percent. This means that this test may miss one out of every twenty previously healthy people who develop tuberculosis. The sensitivity of the TST drops to 80 percent when an immunocompromised person develops tuberculosis. This means that for people with HIV, the TST is not reliable in excluding tuberculosis because it can be negative in 1 in 5 people with HIV infection who develop tuberculosis.

The size of induration required for a positive TST depends on who is being tested. An induration of 5mm is adequate if the person is immunocompromised in any way through disease or from medication. Otherwise an induration of 10mm is required for the test to be regarded as positive.

We would regard a person as being newly infected with tuberculosis when the tuberculin skin test was negative earlier but is positive now. If such a person has no signs of active tuberculosis (after being investigated), the person will be labelled as having latent tuberculosis.

There are situations where a positive TST is not due to latent tuberculosis or to active tuberculosis. BCG vaccination in childhood can result in a positive test for 3 to 5 years after the vaccination. The test can also remain positive for many years after a person has been successfully treated for tuberculosis in the past.

There is a peculiar phenomenon known as the booster phenomenon where a person may develop a positive test simply because of a tuberculin skin test done earlier within the past one year. This phenomenon is because the TST boosts cell mediated immunity that had previously waned. It occurs in people who had tuberculosis earlier. The danger in not being aware of this phenomenon is that we may label such patients as having latent tuberculosis because of the recent conversion in the TST.

To overcome the problem of misinterpreting the TST in people (like health care workers) who may undergo annual tuberculin skin testing, we can do the two-step tuberculin skin test. The details of how this test is done is given in the reference below.

References:
1. The two-step tuberculin skin test
2. Tuberculin skin testing