Ignaz Semmelweis presented empirical evidence showing that cleanliness reduced post-delivery mortality. Medical community of the time would hear none of it: if he couldn't explain himself in theoretical terms his points were invalid, they thought. Furthermore, implying doctors' own fault in introducing disease by being dirty was certainly perceived as an insult. Only several decades later did his views become understood and rooted in a new understanding of disease which shifted the blame from 'polluted air' or 'miasma' to germs.
When Louis Pasteur suggested that microbes responsible for gangrene might be eliminated by using certain chemical solutions, Joseph Lister began experimenting. His work resulted in a new protocol for working in the operating room which included clean clothes, gloves, and medical equipment sterilized by a 5% carbolic acid solution. As the germ theory of disease gained credibility and doctors realized that by not allowing free passage to bacteria one could markedly reduce infection rates, Lister's idea of sterile surgery became the norm.
When Louis Pasteur suggested that microbes responsible for gangrene might be eliminated by using certain chemical solutions, Joseph Lister began experimenting. His work resulted in a new protocol for working in the operating room which included clean clothes, gloves, and medical equipment sterilized by a 5% carbolic acid solution. As the germ theory of disease gained credibility and doctors realized that by not allowing free passage to bacteria one could markedly reduce infection rates, Lister's idea of sterile surgery became the norm.
One would think that 152 years after Semmelweis published his nominal ‘Die Aetiologie, der Begrif und die Prophylaxis des Kindbettfiebers’ (Etiology, Concept and Prophylaxis of Childbed Fever) and 146 years after Lister's Antiseptic Principle of the Practice of Surgery, death from infections in hospitals would be completely eliminated. Nothing is ever so simple, however. Enter sepsis.
Severe inflammatory response syndrome (SIRS) with a suspected or confirmed microbial etiology, sepsis, in its severe form contributes to over 250,000 annual deaths in North America and even more in Europe. A review by Greg S. Martin reveals that
"applying the consensus conference definition, rough estimates of fatality rates (the percentage of patients who die) are as follows:Despite the risk of death due to sepsis today being lower than before, higher incidence rates result in more people than ever dying from sepsis. It seems counter-intuitive in the age when all but a few infectious diseases remain as dangerous as they have been, to see more people dying from an infectious cause than before. Why is it this way? Understanding and increasing awareness of sepsis is crucial in this day and age for health-care professionals and general public alike.
Sepsis: 10–20%
Severe sepsis: 20–50%
Septic shock: 40–80%"
Pathophysiology of sepsis is based on malfunctioning of the immune response and is therefore seen most often in immunocompromised patients, such as those suffering from AIDS or elderly people with underlying chronic morbidities. To put it simply, components of the immune system react vigorously by releasing pro-inflammatory molecules (cytokines, chemokines) in hope of containing an infection but end up harming the host rather than protecting it. It's not the whole story though; untimely death of leukocytes by apoptosis and/or necrosis and problems with coagulation have been noted to greatly contribute to sepsis.
When bacteria (or other pathogens) are first noted inside our body, parts of them called Pathogen-Associated Molecular Patterns (PAMPs) bind to Toll-like receptors on leukocytes. Macrophages polarize to an M1 phenotype (pro-inflammatory) and release pro-inflammatory cytokines such as interleukin-1(beta), tumor necrosis factor (TNF), interleukin-6; mast cells contribute histamine.
Cytokines stimulate endothelial cells to produce adhesion molecules. White blood cells latch onto these molecules and pass through from the blood into infected tissue. Phagocytes (resident macrophages and travelling neutrophils) engulf pathogens and degrade them inside. If pathogens are numerous enough though they can escape phagocytosis. When some pathogens remain lying around cytokines will continue to be released and an inflammatory response will continue to escalate.
With a serious enough infection it's possible that a response against pathogens will be so strong so as to become more deleterious to the host rather than the invader. For example, histamine is responsible for making blood vessels more permeable and therefore useful in getting white blood cells to infected tissues. However, during sepsis it is released systemically and causes the majority of blood vessels to become leaky, which results in severe hypotension. Therefore even if inflammation is detrimental it could be unwise to prescribe anti-inflammatory medication because it's necessary to battle infection. It can only be said that inflammation is causing damage and not whether this inflammation is called or uncalled for.
Adaptive immunity also plays a role. Antigens are presented to T cells by antigen presenting cells (APCs), among other things, which in turn stimulate CD4+ T cells to release cytokines and further develop an orderly immune response. There's often a decline in T cell number in septic patients, which is not unexpected especially in immunocompromised individuals.
Increase in the rate of apoptosis could be responsible for this. More apoptosis was found in the spleen and thymus of septic patients. It was later shown that particularly CD4+ T cells and dendritic cells suffered most apoptosis. The degree of apoptosis was positively correlated with severity of sepsis and its outcome.
On another side of the spectrum, neutrophils show decreased rate of apoptotic death. Their infrequent apoptosis could contribute to organ damage by continuous release of toxic materials.
The last part of pathophysiology I'd like to discuss is coagulation. It was noted in the review that while dysfunctions of coagulation are present in sepsis, nothing beyond this can be said with certainty. What is accepted is that inappropriate intravascular fibrin deposition occurs. I'd like to briefly present what this means.
Fibrin is the end product of coagulation which traps blood cells and constitutes a clot. In sepsis however, fibrin is produced quickly and markedly in small blood vessels. During this process small blood clots form. This causes a condition known as disseminated intravascular coagulation, DIC. These blood clots result in hypoperfusion to organs around which they form and often result in organ dysfunction since organs don't have the opportunity to remove waste and receive nutrients and oxygen. Furthermore, by using up all the clotting factors it leaves other places vulnerable to uncontrollable bleeding, mainly in the GI tract, respiratory system.
So what symptoms can such pathophysiology precipitate?
Symptoms of SIRS include
deviations from normal temperature (either hypothermia, <36C or hyperthermia, >38C)
Heart rate >90 BPM
Respiratory rate >20 per minute
WBC count >12 K or <4 K per cubic millimeter
Stepping up to a more serious stage, sepsis with
one of more dysfunctioning organ system is called severe sepsis. For example, urine output decreases since filtration cannot
occur properly in the kidney with hypotension due to excess fluid leakage from overly permeable blood vessels all over the body.
Liver dysfunction and altered mental status are also possible.
Liver dysfunction and altered mental status are also possible.
Septic
shock occurs when sepsis presents with hypotension unresponsive to given fluids. It is a life-threatening condition and the most serious
complication of sepsis. The heart cannot keep working so cardiac output
plummets, organs can't maintain homeostasis and myocardial infarction
occurs, among other things, resulting in death.
Increased incidence
of sepsis can be attributed to an aging population (particularly in the U.S. and Europe) with chronic underlying illnesses, ever increasing number of medical procedures
performed and more time spent with catheters, escalating drug-resistance among infectious agents.
Treatment
for sepsis is crucial and must be administered as quickly as possible.
Antimicrobial agents, removal of the source of infection (i.e. medical equipment),
also hemodynamic, respiratory and metabolic support must be applied depending
on severity and symptoms.
Once
developed it is extremely difficult to combat, therefore prevention offers the
best opportunity to reduce morbidity and mortality from severe sepsis and
septic shock. Reduction of unnecessary medical procedures, using antiseptics
and avoiding nosocomial infections is of utmost importance.
So perhaps it's not so strange that we face grave danger from sepsis. While even today doctors do not wash their hands as often as is required and nosocomial infections still arise in hospitals, sepsis is a killer unlike other infectious diseases. When we talk about an increasingly old age and number of medical procedures as causes of a disease, we acknowledge our achievements in other aspects of medicine. Just as many people didn't get cancer when average life expectancy of a person was around 40, perhaps increasing incidence of sepsis also shows us that we have reached a point in medical development when the greatest maladies are starting to be forgotten and we are being forced to focus our attention on conditions which were previously overshadowed by even more vicious killers.
P.S. Sepsis is a tough nut to crack. Recently it was shown that mouse models of sepsis are unhelpful when modeling sepsis in humans. Who knows what alterations to our currently accepted mechanism might be for us to discover in the future.
References:
1. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol. 2011;6:19-48. doi: 10.1146/annurev-pathol-011110-130327.
2. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6. doi: 10.1586/eri.12.50.
3. Longo et al. Harrison's Principles of Internal Medicine 18th ed.
So perhaps it's not so strange that we face grave danger from sepsis. While even today doctors do not wash their hands as often as is required and nosocomial infections still arise in hospitals, sepsis is a killer unlike other infectious diseases. When we talk about an increasingly old age and number of medical procedures as causes of a disease, we acknowledge our achievements in other aspects of medicine. Just as many people didn't get cancer when average life expectancy of a person was around 40, perhaps increasing incidence of sepsis also shows us that we have reached a point in medical development when the greatest maladies are starting to be forgotten and we are being forced to focus our attention on conditions which were previously overshadowed by even more vicious killers.
P.S. Sepsis is a tough nut to crack. Recently it was shown that mouse models of sepsis are unhelpful when modeling sepsis in humans. Who knows what alterations to our currently accepted mechanism might be for us to discover in the future.
References:
1. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol. 2011;6:19-48. doi: 10.1146/annurev-pathol-011110-130327.
2. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6. doi: 10.1586/eri.12.50.
3. Longo et al. Harrison's Principles of Internal Medicine 18th ed.
