Sepsis risk spikes with discontinuation of biologics.
Patients with rheumatoid arthritis (RA) who were being treated with biologic therapies and developed serious infections had a lower risk of sepsis than if they were on conventional agents, German researchers reported.
Among patients on biologics at the time of the infection, the risk of sepsis was almost halved, with an odds ratio of 0.56 (95% CI 0.38 to 0.81), according to Anja Strangfeld, MD, of the German Rheumatism Research Center in Berlin, and colleagues.
Sepsis results from a dysregulation of the inflammatory response following exposure to an infectious agent. It “is a major concern in patients with serious infections because it results in a case fatality rate of 30 to 50%. Older patients are particularly susceptible to sepsis because of hospitalization, comorbidity, and impaired physical function,” the researchers wrote in the September Annals of the Rheumatic Diseases.
Patients with RA are at increased risk of infections, and this is further elevated by the use of immunosuppressive therapies — including biologics — as well as disease comorbidities and complications of joint surgeries.
Several decades ago it was shown that tumor necrosis factor (TNF) was a key player in the cascade of events comprising sepsis, but early clinical trials using TNF inhibitors found no survival benefit, until an animal study suggested that the timing of anti-TNF exposure was crucial for ensuring survival following infection.
None of the earlier trials examined whether being on TNF inhibition at the time of serious infection influenced progression to sepsis, either aiding in recovery or worsening the risk. Therefore, Strangfeld and colleagues analyzed outcomes from the German biologics register, which had enrolled more than 12,000 patients on biologics or conventional disease-modifying anti-rheumatic drugs (DMARDs) by 2013.
Among the cohort, 1,017 serious infections were reported, with the most common being pneumonia, in 28.4%, bone and joint infections in 11.2%, and respiratory tract infections other than pneumonia in 10.3%.
A total of 11.7% progressed to sepsis within 1 month, and the case fatality rate was 63%. Among the patients whose infections did not lead to sepsis, the fatality rate was 6.2%.
Compared with the register cohort in general, patients who developed serious infections were older, had longer duration of disease and greater disease activity, as well as more comorbidities.
In a generalized estimating equations model, older age was associated with a higher risk of both sepsis (OR 1.41 for each 10 years, 95% CI 1.15 to 1.74) and death (OR 2.47, 95% CI 1.61 to 3.79). Underlying chronic renal disease also was associated with an increased risk of sepsis (OR 1.93, 95% CI 1.19 to 3.14), while heart failure was linked with a significantly higher mortality risk (OR 3.56, 95% CI 1.73 to 7.33).
Compared with conventional DMARDs, treatment specifically with a TNF inhibitor at the time of infection lowered the risk of sepsis (OR 0.64, 95% CI 0.42 to 0.97) and death (OR 0.48, 95% CI 0.24 to 0.95). Treatment with other biologic agents also was protective against sepsis (OR 0.45, 95% CI 0.25 to 0.80) and mortality (OR 0.16, 95% CI 0.05 to 0.54).
“The effective immunosuppression via biologic DMARDs may prevent an unregulated host response to serious infection and the development of sepsis,” Strangfeld and colleagues stated.
The researchers then compared outcomes among patients who had not previously received a biologic at the time of the infection (n=134), those who were on a biologic (n=517), and those who had been on a biologic but stopped it more than a month before (n=212).
There were 133 serious infections in the biologics-naive group, 515 in the current biologics group, and 211 in the biologics-discontinued group. Sepsis developed in 17.3% of the biologics-naive group and in 18.4% of the biologics-discontinued group, compared with 11.3% of patients currently on biologics.
After adjustment for age, sex, steroid dose, physical function, and comorbidities, the odds ratios for sepsis (OR 0.97, 95% CI 0.56 to 1.70) and death (OR 0.96, 95% CI 0.42 to 2.17) among those who had discontinued biologics did not differ from those who had never received a biologic.
In contrast, the adjusted risk for sepsis (OR 0.57, 95% CI 0.34 to 0.97) and death (OR 0.34, 95% CI 0.15 to 0.80) was significantly lower for those currently receiving a biologic compared with those never given biologics.
The impact of discontinuation of biologic therapy on sepsis was an important finding of the study, according to the authors.
“It is common knowledge that initiation of biologic DMARD therapy increases the risk of serious infections. Further, discontinuation of biologic DMARDs is supposed to decrease the risk of serious infection,” they wrote.
“Our results suggest a different mechanism: adverse outcomes of serious infections (sepsis and death) were more likely in biologics-naive patients than in patients exposed to biologic DMARDs at the time of serious infection, which could indicate a protective effect of biologic DMARDs,” they explained. But that protective effect was lost when biologics had been stopped, they pointed out.
“Discontinuation of biologic DMARDs seems to shift the risk from an increased susceptibility to serious infections to more severe outcomes,” they observed.
However, the results of this study need to be confirmed.
A limitation of the study was the possibility of “suspicion bias,” with patients on biologic therapies possibly being hospitalized more quickly and followed more closely if they developed serious infections.
Sepsis, a dangerous outcome triggered by an infection, can be fast-moving, debilitating, and fatal. But that’s not all.
Now researchers are finding that even those who survive tissue damage and organ failure caused by sepsis can have a higher risk of “late death,” defined as mortality within 2 years of being treated for the condition.
Researchers at the University of Michigan Health System are generating new data on the causes of sepsis-related late death, but it is unclear whether the sepsis itself or a pre-existing health problem is driving the elevated mortality rate.
A study in the current issue of the BMJ suggests that pre-existing conditions alone do not account for late death. The findings suggest that “long-term mortality after sepsis could be more amenable to intervention than previously thought,” according to the study.
Researchers found that compared with the patients admitted to the hospital with a non-sepsis infection, patients with sepsis had a 10% absolute increase in late death.
The study also found a 16% absolute increase in late death among sepsis patients compared with those admitted with sterile inflammatory conditions. Sepsis was also associated with a 22% absolute increase in late mortality relative to similar, hospitalized adults.
“Taken together, our findings do not refute the importance of baseline burden of comorbidity to patients’ long-term outcomes after sepsis. They do, however, indicate that sepsis confers an additional risk of late mortality above and beyond that predicted by status before sepsis alone,” the researchers wrote.
The incidence of sepsis among hospitals patients has risen from 621,000 in 2000 to 1,141,000 in 2008, according to the latest figures available from the CDC.
In 2009, the cost of hospital care for sepsis was an estimated $15.4 billion. Between 1997 through 2008, costs for treating patients hospitalized for sepsis increased by an average of 11.9% each year. Efforts are underway to promote early diagnosis and treatment of the condition.
In order to explore the question of whether the elevated mortality is linked to the sepsis or underlying conditions, the researchers analyzed medical records from the University of Michigan’s Health and Retirement Study (HRS), a long-term national study of more than 20,000 older Americans.
They found that one in five older patients who survives sepsis has a late death not explained by pre-sepsis health status.
“This suggests that more than one in five patients who survives sepsis dies acutely within the next 2 years as a consequence of sepsis. Compared with patients admitted to hospital with non-sepsis infection or sterile inflammatory conditions, patients with sepsis experienced a 10% increase in late mortality — or roughly one in 10 had a late death related to sepsis,” according to the study.
Sepsis is also a major cause of hospital readmissions, and ongoing research is looking at risk factors. A 2015 study found 30-day readmission rates for sepsis for one in five patients in California.
New evidence highlights the importance of the liver in immunity against bacterial pneumonia. The study is the first of its kind to directly show such a link between liver-produced molecules and pneumonia susceptibility during sepsis.
Led by researchers at Boston University School of Medicine (BUSM), the study appears in the journal Infection and Immunity.
Pneumonia, according to the World Health Organization, is the leading infectious cause of death in children worldwide, taking more than 900,000 lives of children under the age of 5 in 2013 alone. Pneumonia, in both children and adults, is frequently associated with sepsis, which is the body’s own inflammatory reaction to becoming infected.
In order to model the common clinical scenario of sepsis followed by pneumonia, models were systemically treated with a bacterial product (eliciting a sepsis-like response) followed hours later by a live bacterial challenge in the lungs. One group had completely normal livers, and the other lacked a gene in their livers that prevented maximal liver activation. The researcher found the group lacking a complete liver response was more likely to succumb to pneumonia, exhibiting a significantly compromised immune response in both the lungs and blood, where more bacteria survived.
According to the researchers there is a well-established link between pneumonia and sepsis, such that both increase the likelihood of the other. Both also activate the liver to initiate what is known as the acute phase response, an event leading to the liver’s production of acute phase proteins that change in the blood “These proteins are frequently used as clinical biomarkers, but their combined biological significance is mostly speculative. However, the results of this study directly suggest that liver activation is required to maintain adequate immune responses in the lungs,” explained corresponding author Lee J. Quinton, PhD, associate professor of medicine and pathology at BUSM.
While it may be too early to immediately speculate on the applications of these findings, the authors believe that liver activity may serve as a previously unappreciated window into pneumonia defense/susceptibility. “A better understanding of how these distinct organs collaborate to mount immune responses has important clinical implications for patients with or at risk for pneumonia and sepsis. The idea that non-lung tissue could be targeted for treatments of lung disease is compelling,” added Quinton.
By Dr Ron Daniels, CEO of the UK Sepsis Trust and Global Sepsis Alliance
A decade ago, I met a man who would come not only to define my career, but to change my life. Jem would never know the extent of his influence, because when I met him, he was in an induced coma. Sepsis had taken a strong 37-year-old man and reduced him to a wreck of failing organs in a matter of hours.
I encounter sepsis daily as an Intensive Care doctor, and who knows why Jem was the one to make me resolve to fight this indiscriminate killer, which claims an estimated 37,000 in the UK every year.
But resolve I did, and ten years later we are saving lives. I’m privileged now to have met hundreds of adults and children affected by sepsis and their families. These aren’t just statistics. These are people who are loved. They have stories like mine. Stories like yours. Stories like the one Amanda Prowse has written for her tenth novel, “Three-and-a-Half-Heartbeats”.
It tells the heart-breaking story of a young couple, Grace and Tom Penderford, who had a strong marriage, a comfortable home, and a healthy baby girl. But soon after Chloe turns three, tragedy strikes and sepsis takes her life.
The Penderfords had never heard of sepsis – the condition which globally kills someone, somewhere every three-and-a-half seconds. In the UK, around 1,000 children die from the condition each year – a fifth of all child deaths.
Awareness is the number one cure for sepsis. Raising recognition of the disease and increasing the number of patients treated in the ‘Golden Hour’ is the single biggest attempt we can make to save lives.
With public education, better knowledge and awareness among doctors, nurses and paramedics, and by redesigning the way patients with sepsis are treated, I know we can save 12,500 lives per year in the UK and shave £170 million from the NHS budget.
All the proceeds from the novel are going to the UK Sepsis Trust, which I run along with the help of an army of volunteers from the medical profession and those who’ve been affected. If you would like to help, please buy Amanda Prowse’s e-book, “Three-and-a-Half Heartbeats”. It costs just £1.89 and a copy of the book, which launches on September 10, can be pre-ordered here.
Researchers at Duke Medicine have determined that kidney function plays a critical role in the fate of patients being treated for sepsis, a potentially life-threatening complication of an infection.
In a study published May 20, 2015, in the journal Kidney International, Duke researchers and their colleagues identified physiological changes at the molecular level that might be affected by acute kidney injury. The findings could help physicians improve hemodialysis practices, increasing patient survival rates after kidney failure.
Acute kidney injury is a serious and common health complication, occurring in up to 20 percent of all hospitalized patients and more than 45 percent of patients in a critical-care setting, according to the National Institutes of Health.
“There are a lot of things that we assume to be true about the impact of acute kidney injury on patients,” said lead author Ephraim Tsalik, M.D., Ph.D., assistant professor at Duke University School of Medicine. “This study is the first to comprehensively characterize what is happening at the patient level, potentially as a cause and a consequence of acute kidney injury that we see in the setting of critical illness.”
Sepsis, which is defined as systemic inflammation resulting from an infection, often results in an abrupt decrease in the kidney’s ability to effectively filter the blood.
The Community Acquired Pneumonia and Sepsis Outcome Diagnostic (CAPSOD) study, led by Stephen Kingsmore, M.B, D.Sc., of Children’s Mercy Hospitals and Clinic, was initially created as a repository for patients visiting the emergency department with suspected sepsis. The researchers used clinical and molecular information generated in the CAPSOD study to correlate patient-level data with changes in molecular markers in the blood.
They found that kidney function was a major determinant of how a patient responded to treatment for sepsis.
“We have over 2,000 patients enrolled in the CAPSOD repository,” Tsalik said. “We are trying to use new tools to ask why is it that some patients show up and get sicker, despite getting all the right treatment, and why some patients show up, get the right treatment, and quickly get better.”
Using an “‘omics-based” approach, the researchers looked at variations in metabolite level, protein production, and gene expression in the blood in 150 patients with critical illness. The study design also allowed the researchers to investigate what impact hemodialysis, a medical treatment for kidney failure that filters toxins from the blood, was having on a variety of molecular markers.
“Rather than setting out to prove existing hypotheses, this study was designed to identify new questions or associations we were not previously aware of,” Tsalik said. “There were a number of things that we expected to see and did, such as the accumulation of molecules normally cleared by the kidney among patients with kidney dysfunction.”
Those known molecules are usually filtered out when a patient is receiving hemodialysis; however, the researchers also identified other chemicals and metabolites that were not previously shown to be abnormal in patients on hemodialysis.
“It may be that these newly implicated metabolites are not clinically relevant, but by identifying them, we’ve opened up opportunities for researchers to see if they cause toxicity to the patient,” Tsalik said. “We want to understand how to improve the care of patients with acute kidney injury and those requiring hemodialysis.”
The Efficacy and Safety of Plasma Exchange in Patients With Sepsis and Septic Shock: A Systematic Review and Meta-analysis
Rimmer E, Houston BL, Kumar A, et al
Plasma Exchange in Sepsis
Sepsis is a common medical condition and the most common cause of death among critically ill patients.[1,2] Plasma exchange separates plasma from whole blood and exchanges the plasma with normal saline, albumin, or fresh frozen plasma. Plasma exchange thus could improve sepsis outcomes through removal of harmful substances or by replacement of depleted blood components.
Rimmer and colleagues sought to determine whether plasma exchange was associated with improved outcomes by conducting a systematic review of the literature (MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, etc) focusing on randomized trials of patients receiving plasma exchange as part of therapy for septic shock. They found 1957 studies but only four unique trials enrolling a total of 194 patients (one enrolled adults only, two enrolled children only, and one enrolled adults and children).
The use of plasma exchange was associated with a significant reduction in all-cause mortality in adults (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.42-0.96) but not in children (RR, 0.96; 95% CI, 0.28-3.38). None of the trials reported length of intensive care unit or hospital stay. Only one trial reported adverse events associated with plasma exchange, including six episodes of hypotension and one allergic reaction to fresh frozen plasma. The study authors concluded that there is insufficient evidence about plasma exchange for patients with sepsis or septic shock, and randomized controlled trials are required.
This study is very helpful in providing an evidence-based synthesis of data for the effect of plasma exchange as adjunctive therapy in the management of sepsis or septic shock. Not surprisingly, it is difficult to draw definitive conclusions from only four studies (two of which were strictly pediatric trials).[3-6]
However, the data suggest that there could be a benefit to plasma exchange in adults with septic shock, and companies and individual investigators are working to test this further. Given the pathogenesis of sepsis, with increased understanding of the damage resulting from both severe inflammation and anti-inflammation, strategies to modulate the immune response may confer real benefits for these patients, for whom morbidity and mortality remain high. However, whether this strategy is most effectively delivered by plasma exchange or by pharmacologic manipulation of the immune response remains to be seen.
- Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840-851. Abstract
- Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546-1554. Abstract
- Reeves JH, Butt WW, Shann F, et al. Continuous plasmafiltration in sepsis syndrome. Plasmafiltration in Sepsis Study Group. Crit Care Med. 1999;27:2096-2104. Abstract
- Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med. 2002;28:1434–-439. Abstract
- Nguyen TC, Han YY, Kiss JE, et al. Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia associated multiple organ failure. Crit Care Med. 2008;36:2878-2887. Abstract
- Long EJ, Shann F, Pearson G, Buckley D, Butt W. A randomised controlled trial of plasma filtration in severe paediatric sepsis. Crit Care Resusc. 2013;15:198-204. Abstract
A team of Massachusetts General Hospital (MGH) investigators has identified what may be a biomarker predicting the development of the dangerous systemic infection sepsis in patients with serious burns. In their report in the open-access journal PLOS ONE, the researchers describe finding that the motion through a microfluidic device of the white blood cells called neutrophils is significantly altered two to three days before sepsis develops, a finding that may provide a critically needed method for early diagnosis.
“Neutrophils are the major white blood cell protecting us against infection, and a healthy individual has an army of 25 billion circulating neutrophils ready to fight invading pathogens,” explains Daniel Irimia, MD, PhD, associate director of the BioMEMS Resource Center in the MGH Department of Surgery and corresponding author of the PLOS ONE report. “The most common blood test ordered to evaluate a patient’s ability to fight infection is absolute neutrophil count, based on the assumption that – like well-trained soldiers – neutrophils are always fast, disciplined and effective in pursuing their targets, meaning that the size of the neutrophil ‘army’ is all that matters. Our work challenges that assumption and shows that, even when the number of neutrophils is unchanged, the army can fall into disarray and become ineffective.”
Sepsis is the leading cause of death among patients with major burns – those affecting more than 20 percent of body surface – with a mortality rate of 30 percent. It has been calculated that every 6 hours of delay in a sepsis diagnosis decreases the chances of survival by 10 percent. Since the symptoms of sepsis are similar to those of the systemic inflammation that occurs in almost every serious burn patient, diagnosing sepsis relies on culturing bacteria from the blood, a process that takes 12 to 24 hours.
While no previous studies had identified sepsis-associated changes in the motion of neutrophils – which travel to sites of infection in response to chemical signals – the motility or ability to move spontaneously of neutrophils is known to be less efficient in burn patients than in healthy individuals, leading the researchers to wonder whether correlations might exist between changes in neutrophil motility and sepsis in patients with major burns.
To investigate this possibility, the MGH team designed a microfluidic device with channels smaller than the diameter of neutrophils to study the cells’ motion toward a chemical signal. Straight channel sections measured the speed and persistence of the cells’ motion, and divisions and obstacles in the channels tested the cells’ ability to change directions. The researchers then analyzed the ability of neutrophils from blood samples of 13 patients with serious burns, collected several times during their treatment, to move through the device when it was primed with one of two chemical attractants or with saline solution, and compared it with the movement of cells from 3 healthy volunteers.
Neutrophils from healthy individuals moved quickly and efficiently through the device toward a chemical attractant – easily navigating around corners and posts – while cells from burn patients showed limited, slower and poorly organized movement toward the chemical signal. But analyzing movement patterns when the device contained no chemical attractant revealed a surprising finding: neutrophils from patients who had developed or were about to develop sepsis spontaneously moved through the device – like soldiers deciding to advance in the absence of any orders – while those from other patients and from healthy volunteers showed little or no motion.
This movement of neutrophils in the absence of chemical signals was observed in samples taken from some patients several days before a diagnosis of sepsis could be made, and once effective antibiotic treatment began, the unusual movement pattern began to fade. The authors note that, in addition to allowing faster initiation of antibiotic treatment, the ability to diagnose sepsis rapidly and accurately would reduce the inappropriate use of antibiotics that leads to the proliferation of resistant bacteria that is so common in burn units.
“Since only a handful of rare genetic disorders affect neutrophil function, it has long been assumed that studying these cells was not important; but our findings indicate that neutrophils play a much more important role in sepsis than has been appreciated,” says Irimia, an assistant professor of Surgery at Harvard Medical School. “Studies including larger numbers of patients with major burns and more precise measurements are under way. We’re also working to expand this investigation to other patients at risk for sepsis, to see if the findings from burn patients have broader application.”