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A disease of doctors

MagazineMarch 2005 (Vol. 15 Issue 12)A disease of doctors

When we think of pneumonia, we see it as a complicated and dangerous infection caused by bugs 'in the air'

When we think of pneumonia, we see it as a complicated and dangerous infection caused by bugs 'in the air'. But there are a number of disparate, but common, medications that can lead to pneumonia, sometimes fatally. Going into hospital can cause it, too.

What is pneumonia? It's an inflammation of the lungs that we tend to hear little of these days as it's lumped together with things like tuberculosis and rickets - supposedly problems of yesteryear.

But, in fact, pneumonia is on the increase and, in the UK, the number of deaths due to the disease has almost doubled in less than a decade.

Having pneumonia has been described as being like having a cold or the flu, but far more intense. The breathing problems caused by a cold are uncomfortable and may even be incapacitating, but they won't kill you and will normally fade away on their own. Pneumonia, on the other hand, can linger, worsen and, finally, interfere with breathing to the point of being fatal.

Most pneumonia occurs in the winter, typically striking the very young or the over-65s (JAMA, 1995; 274: 134-41). Up to 4 per cent of children in Europe and the US catch pneumonia (Am Fam Physician, 2004; 70: 899-908). It can be brought on by nearly anything that infects the lungs - mainly bacteria, but also viruses, parasites and fungal spores.

Potentially fatal illness
Pneumonia often arrives a few days after an apparently benign cold or sore throat. However, what makes it so serious compared with a cold is that it causes a build-up of fluid in the lungs, thus clogging up the tiny air sacs (alveoli) in the lungs where oxygen is taken from the air and transferred to the bloodstream.

So, it's a lack of oxygen, rather than the infection itself, that causes the high death rate. An additional factor is that as much as 80 per cent of pneumonia-causing bacteria have become resistant to antibiotics (Semin Respir Infect, 2000; 15: 195-207).

Doctors have traditionally classified pneumonia into two types, depending on how you caught it. Until the advent of modern medicine, the most common type was the so-called 'community-acquired' pneumonia (CAP) - something caught from other people.

However, nowadays, running a close second is what's admitted to be 'hospital-acquired pneumonia' (HAP), seen almost exclusively in intensive care units. Up to half of all ICU patients contract pneumonia, among whom 27-50 per cent actually die of the condition (Infect Dis Clin North Am, 1998; 12: 761-79).

Why should hospital ICUs be so hazardous? The major reason is believed to be because ICU patients are often 'ventilated' to help them breathe. This involves forcing an airway tube down the throat, thus bypassing the lungs' primary physical defence against infection - the cough reflex. Bacteria can then enter the lungs unimpeded. Hospital bacteria can be extremely virulent, particularly the 'gram-negative' variety which, because they are not found outside of hospitals, people will have no resistance to. They also tend to be resistant to antibiotics.

HAP is widely acknowledged to be a serious, growing problem, exacerbated by the fact that it's difficult to diagnose (Crit Care Med, 2000; 28: 2799-804). It's also a classic example of an iatrogenic (doctor-caused) condition, but it's not the only one for pneumonia.

Drug-acquired pneumonia
In addition to CAP and HAP, there's now a third one - DAP, drug-acquired pneumonia. So far, at least a half-dozen types of medications have been found to cause pneumonia-like lung inflammation. Last month (WDDTY vol 15 no 10), we featured the latest research showing that everyday antiulcer drugs such as Tagamet, Zantac and Losec have been responsible for a doubling of pneumonia cases, particularly among older patients (JAMA, 2004; 292: 1955-60).

Some doctors dismiss the findings as a statistical fluke, but US gastroenterologist Dr Jay Marks disagrees. "It is interesting to note that two types of antacid drugs which work by different mechanisms to reduce the production of acid by the stomach are both associated with pneumonia," he says. "This makes the association more likely to be causal."

But why should stomach medications affect the lungs? According to the Dutch researchers who made this discovery, antacids cause pneumonia probably because normal stomach acid is a powerful natural defence against infection, destroying a wide range of harmful bacteria and viruses, but antacid drugs neutralise stomach acids, thus allowing pathogens in the stomach to travel up the oesophagus and into the lungs.

"These drugs are not as safe as everybody thinks," says lead researcher Dr Robert Laheij of Nijmegen University. "If it is not necessary for you to use them, don't. Keep in mind that these medicines can have serious side-effects - especially in more fragile patients who can have serious problems."

This is a timely finding, as antacids have become some of the world's most widely prescribed drugs, with annual sales worth about $16 billion. Moreover, in the US, many of these drugs are now available without a doctor's prescription so, unless people are warned off them, we can expect to see a further hike in the number of pneumonia cases.

Another commonly prescribed drug that can cause pneumonia is the antibiotic nitrofurantoin (Macrodantin, Macrobid). This is the treatment of choice for urinary tract infections, and is generally considered so benign that it is routinely given to children. However, it comes with a wide range of nasty side-effects, most of which attack the respiratory system. These can arise within as little as a few days of starting the drug, but may last indefinitely - even when the antibiotic is stopped (Scand J Respir Dis, 1977; 58: 41-50). Cases of nitrofurantoin-induced pneumonia have been severe enough to require hospital treatment, and some have proved fatal (Chest, 1989; 96: 512-5).

Quite why this antibiotic should be so toxic to the lungs is not clear, but it's believed to be a sensitivity reaction leading to localised inflammation (Scand J Respir Dis, 1977; 58: 41-50).

Heart drugs and pneumonia
A totally different chemical is the heart drug amiodarone (Cordarone), yet it, too, can cause pneumonia. Amiodarone is one of the top drugs prescribed for arrhythmias, as it acts directly on heart muscle to slow nerve impulses and regularise heartbeats. However, it has also been described as one of the riskiest heart drugs around, as its side-effects cause "an acute pulmonary syndrome that looks and acts just like typical pneumonia", according to US cardiologist Dr Richard Fogoros. It produces "foamy alveolar macrophages" that fill the air spaces in the lungs, causing a sudden cough and shortness of breath.

This usually goes away on stopping the drug but, in some cases, the problem persists. "This second form is more insidious," says Dr Fogoros. "It is a gradual, unnoticeable 'stiffening' of the lungs that both the doctor and patient can overlook - until finally severe, probably irreversible, lung damage is done."

Again, precisely how the drug causes such havoc isn't clear. What's known is that it tends to concentrate in the chest area and is a persistent chemical, taking weeks to be eliminated from the body. The pneumonia it causes can be fatal (Thorax, 1984; 39: 57-64).

A third pneumonia-causing drug is the powerful anticancer agent methotrexate, also widely used in low doses against arthritis and severe psoriasis. It is thought to work by interfering with cell growth and suppressing the immune system. In about one in 20 patients, the drug has been found to attack the lungs, causing a range of conditions, including pneumonia.

What has surprised researchers is the rapidity and virulence of the drug's side-effects. Pneumonia can be triggered after as little as two months of therapy, and by doses as low as 5 mg a week (Rev Rhum Engl Ed, 1996; 63: 453-6). Furthermore, the pneumonia may be irreversible, so that even stopping the methotrexate will not sort out the problem. A significant number of cases end in death, even with the very low doses (15 mg/week for a month) used for psoriasis (Mil Med, 2004; 169: 298-300).

Acne is another relatively minor skin condition that can also lead to pneumonia if treated by some prescription drugs. The antibiotic minocycline (Minocin) is a common treatment for acne, but it, too, can cause "various pulmonary complications", including pneumonia characterised by "relapsing acute respiratory failure" (Chest, 2003; 123: 2146-8).

Why drugs cause pneumonia
How is it that so many disparate drugs can cause such similar problems? According to French experts, there's a wide range of explanations - from inflammation and swelling of lung tissue to outright lung cell poisoning (Rev Mal Respir, 1996; 13: 127-32).

In fact, it now turns out that the lungs are especially sensitive to a whole host of prescribed drugs - not just antibiotics, heart and arthritis medications, but also milder drugs such as antidepressants, appetite suppressants and even aspirin (see lower box). "Drug-induced lung disease is a major source of iatrogenic injury," say doctors at the Department of Pulmonary Care in the Cleveland Clinic. "In 1972, only 19 drugs were known to cause pulmonary disease. Now, at least 150 agents are recognised, and the list continues to grow" (Cleve Clin J Med, 2001; 68: 782-5, 789-95).

This is disturbing enough, but now comes the news that lung disease may be even more dangerous than we thought. Experts from a number of UK hospitals voiced their concerns in a landmark analysis of the medical records of 40,000 patients. They found an association between respiratory problems such as pneumonia and a subsequent heart attack or stroke - in fact, a fivefold increase in risk.

What lung infections apparently do is disturb the fat/plaque buildup in arteries, turning a theoretical problem into a killer disease (N Engl J Med, 2004; 351: 2599-610).

Among the chief investigators was Professor Patrick Vallance of University College London, who put it like this: "After the age of 50, we all have some degree of furring up in the arteries, but most of the time, it sits there fairly harmlessly. However, during infection, stable deposits become unstable and may break off, causing blockages that may lead to a heart attack or stroke."

This means that drugs that cause pneumonia as a side-effect may be more dangerous than we thought - even those seemingly benign (and profitable) antacids such as Tagamet and Zantac. Professor Vallance hasn't yet made the connection to drug-induced pneumonia - but we have.

On studying the available published mortality statistics for the major antacid ulcer drugs, we've found a consistent pattern. As soon as people start taking these drugs, the death rate soars. For H2 antagonists such as cimetidine (Tagamet), the rate doubles to a 90 per cent increase in fatalities in the first year (Gut, 1992; 33: 1280-4). For the three major proton-pump inhibitors (omeprazole, esomeprazole and lansoprazole), there's an overall 60 per cent increase in non-ulcer deaths (J Gastroenterol Hepatol, 2005; 20: 11-25); omeprazole (Losec) is associated with a 44 per cent increase in deaths in year one, some of which are 'circulatory diseases' (Gut, 2003; 52: 942-6).

This confirms that ulcer drugs may, as Professor Vallance's analysis suggests, turn a latent arterial disease into a killer - and all through pneumonia, a disease we thought we had done with years ago.

Tony Edwards


No sense of smell

What is pneumonia?

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