Infectious Diseases

The Food and Drug Administration has invited submission of pathogen samples for its Database for Reference Grade Microbial Sequences (FDA-ARGOS), which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.

Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.

However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.

[email protected]

The Food and Drug Administration has invited submission of pathogen samples for its Database for Reference Grade Microbial Sequences (FDA-ARGOS), which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.

Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.

However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.

[email protected]

The Food and Drug Administration has invited submission of pathogen samples for its Database for Reference Grade Microbial Sequences (FDA-ARGOS), which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.

Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.

However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.

[email protected]

Acute graft-vs-host disease (GVHD) is a T-cell mediated immunogenic response in which T lymphocytes from a donor regard host tissue as foreign and attack it in the setting of immunosuppression.¹ The most common cause of acute GVHD is allogeneic stem cell transplantation, with solid-organ transplantation being a much less common cause.² The incidence of acute GVHD following orthotopic liver transplantation (OLT) is 0.1%, as reported by the United Network for Organ Sharing, compared to an incidence of 40% to 60% in hematopoietic stem cell transplant recipients.^3,4

Early recognition and treatment of acute GVHD following liver transplantation is imperative, as the mortality rate is 85% to 90%.² We present a case of acute GVHD in a liver transplantation patient, with a focus on diagnostic criteria and comparison to acute GVHD following hematopoietic stem cell transplantation.

Case Report

A 68-year-old woman with a history of hepatitis C virus infection, hepatocellular carcinoma, and OLT 1 month prior presented to the hospital with fever and abdominal cellulitis in close proximity to the surgical site of 1 week’s duration. The patient was started on vancomycin and cefepime; pan cultures were performed.

At 10 days of hospitalization, the patient developed a pruritic, nontender, erythematous rash on the abdomen, with extension onto the chest and legs. The rash was associated with low-grade fever but not with diarrhea. Physical examination was notable for a few erythematous macules and scattered papules over the neck and chest and a large erythematous plaque with multiple ecchymoses over the lower abdomen (Figure 1A). Erythematous macules and papules coalescing into plaques were present on the lower back (Figure 1B) and proximal thighs. Oral, ocular, and genital lesions were absent.

Over a 2-day period, the rash progressed to diffuse erythematous papules over the chest (Figure 2A) and bilateral arms (Figure 2B) including the palms. The patient also developed erythematous papules over the jawline and forehead as well as confluent erythematous plaques over the back with extension of the rash to involve the legs. She also had erythema and swelling bilaterally over the ears. She reported diarrhea. The low-grade fever resolved.

Comment

GVHD Subtypes
The 2 types of GVHD are humoral and cellular.⁵ The humoral type results from ABO blood type incompatibility between donor and recipient and causes mild hemolytic anemia and fever. The cellular type is directed against major histocompatibility complexes and is associated with high morbidity and mortality.

Presentation of GVHD
Acute GVHD following OLT usually occurs 3 to 5 weeks after transplantation,⁶ as in our patient. Symptoms include rash, fever, pancytopenia, and diarrhea.² Skin is the most commonly involved organ in acute GVHD; rash is the earliest manifestation.¹ The rash can be asymptomatic or associated with pain and pruritus. Initial cutaneous manifestations include palmar erythema and erythematous to violaceous discoloration of the face and ears. A diffuse maculopapular rash can develop, involving the face, abdomen, and trunk. The rash may progress to formation of bullae or skin sloughing, resembling Stevens-Johnson syndrome or toxic epidermal necrolysis.¹ The skin manifestation of acute GVHD following OLT is similar to hematopoietic stem cell transplantation (Table).^7,8

Prevention
Acute GVHD following OLT can be prevented by eliminating donor T lymphocytes from the liver before transplantation. However, because the incidence of acute GVHD following OLT is very low, this approach is not routinely taken.²

Conclusion

Acute GVHD following liver transplantation is a rare complication; however, it has high mortality, necessitating further research regarding treatment and prevention. Early recognition and treatment of this condition can improve outcomes. Dermatologists should be familiar with the skin manifestations of acute GVHD following liver transplantation due to the rising number of cases of solid-organ transplantation.

Acute graft-vs-host disease (GVHD) is a T-cell mediated immunogenic response in which T lymphocytes from a donor regard host tissue as foreign and attack it in the setting of immunosuppression.¹ The most common cause of acute GVHD is allogeneic stem cell transplantation, with solid-organ transplantation being a much less common cause.² The incidence of acute GVHD following orthotopic liver transplantation (OLT) is 0.1%, as reported by the United Network for Organ Sharing, compared to an incidence of 40% to 60% in hematopoietic stem cell transplant recipients.^3,4

Early recognition and treatment of acute GVHD following liver transplantation is imperative, as the mortality rate is 85% to 90%.² We present a case of acute GVHD in a liver transplantation patient, with a focus on diagnostic criteria and comparison to acute GVHD following hematopoietic stem cell transplantation.

Case Report

A 68-year-old woman with a history of hepatitis C virus infection, hepatocellular carcinoma, and OLT 1 month prior presented to the hospital with fever and abdominal cellulitis in close proximity to the surgical site of 1 week’s duration. The patient was started on vancomycin and cefepime; pan cultures were performed.

At 10 days of hospitalization, the patient developed a pruritic, nontender, erythematous rash on the abdomen, with extension onto the chest and legs. The rash was associated with low-grade fever but not with diarrhea. Physical examination was notable for a few erythematous macules and scattered papules over the neck and chest and a large erythematous plaque with multiple ecchymoses over the lower abdomen (Figure 1A). Erythematous macules and papules coalescing into plaques were present on the lower back (Figure 1B) and proximal thighs. Oral, ocular, and genital lesions were absent.

Over a 2-day period, the rash progressed to diffuse erythematous papules over the chest (Figure 2A) and bilateral arms (Figure 2B) including the palms. The patient also developed erythematous papules over the jawline and forehead as well as confluent erythematous plaques over the back with extension of the rash to involve the legs. She also had erythema and swelling bilaterally over the ears. She reported diarrhea. The low-grade fever resolved.

Comment

GVHD Subtypes
The 2 types of GVHD are humoral and cellular.⁵ The humoral type results from ABO blood type incompatibility between donor and recipient and causes mild hemolytic anemia and fever. The cellular type is directed against major histocompatibility complexes and is associated with high morbidity and mortality.

Presentation of GVHD
Acute GVHD following OLT usually occurs 3 to 5 weeks after transplantation,⁶ as in our patient. Symptoms include rash, fever, pancytopenia, and diarrhea.² Skin is the most commonly involved organ in acute GVHD; rash is the earliest manifestation.¹ The rash can be asymptomatic or associated with pain and pruritus. Initial cutaneous manifestations include palmar erythema and erythematous to violaceous discoloration of the face and ears. A diffuse maculopapular rash can develop, involving the face, abdomen, and trunk. The rash may progress to formation of bullae or skin sloughing, resembling Stevens-Johnson syndrome or toxic epidermal necrolysis.¹ The skin manifestation of acute GVHD following OLT is similar to hematopoietic stem cell transplantation (Table).^7,8

Prevention
Acute GVHD following OLT can be prevented by eliminating donor T lymphocytes from the liver before transplantation. However, because the incidence of acute GVHD following OLT is very low, this approach is not routinely taken.²

Conclusion

Acute GVHD following liver transplantation is a rare complication; however, it has high mortality, necessitating further research regarding treatment and prevention. Early recognition and treatment of this condition can improve outcomes. Dermatologists should be familiar with the skin manifestations of acute GVHD following liver transplantation due to the rising number of cases of solid-organ transplantation.

Acute graft-vs-host disease (GVHD) is a T-cell mediated immunogenic response in which T lymphocytes from a donor regard host tissue as foreign and attack it in the setting of immunosuppression.¹ The most common cause of acute GVHD is allogeneic stem cell transplantation, with solid-organ transplantation being a much less common cause.² The incidence of acute GVHD following orthotopic liver transplantation (OLT) is 0.1%, as reported by the United Network for Organ Sharing, compared to an incidence of 40% to 60% in hematopoietic stem cell transplant recipients.^3,4

Early recognition and treatment of acute GVHD following liver transplantation is imperative, as the mortality rate is 85% to 90%.² We present a case of acute GVHD in a liver transplantation patient, with a focus on diagnostic criteria and comparison to acute GVHD following hematopoietic stem cell transplantation.

Case Report

A 68-year-old woman with a history of hepatitis C virus infection, hepatocellular carcinoma, and OLT 1 month prior presented to the hospital with fever and abdominal cellulitis in close proximity to the surgical site of 1 week’s duration. The patient was started on vancomycin and cefepime; pan cultures were performed.

At 10 days of hospitalization, the patient developed a pruritic, nontender, erythematous rash on the abdomen, with extension onto the chest and legs. The rash was associated with low-grade fever but not with diarrhea. Physical examination was notable for a few erythematous macules and scattered papules over the neck and chest and a large erythematous plaque with multiple ecchymoses over the lower abdomen (Figure 1A). Erythematous macules and papules coalescing into plaques were present on the lower back (Figure 1B) and proximal thighs. Oral, ocular, and genital lesions were absent.

Over a 2-day period, the rash progressed to diffuse erythematous papules over the chest (Figure 2A) and bilateral arms (Figure 2B) including the palms. The patient also developed erythematous papules over the jawline and forehead as well as confluent erythematous plaques over the back with extension of the rash to involve the legs. She also had erythema and swelling bilaterally over the ears. She reported diarrhea. The low-grade fever resolved.

Comment

GVHD Subtypes
The 2 types of GVHD are humoral and cellular.⁵ The humoral type results from ABO blood type incompatibility between donor and recipient and causes mild hemolytic anemia and fever. The cellular type is directed against major histocompatibility complexes and is associated with high morbidity and mortality.

Presentation of GVHD
Acute GVHD following OLT usually occurs 3 to 5 weeks after transplantation,⁶ as in our patient. Symptoms include rash, fever, pancytopenia, and diarrhea.² Skin is the most commonly involved organ in acute GVHD; rash is the earliest manifestation.¹ The rash can be asymptomatic or associated with pain and pruritus. Initial cutaneous manifestations include palmar erythema and erythematous to violaceous discoloration of the face and ears. A diffuse maculopapular rash can develop, involving the face, abdomen, and trunk. The rash may progress to formation of bullae or skin sloughing, resembling Stevens-Johnson syndrome or toxic epidermal necrolysis.¹ The skin manifestation of acute GVHD following OLT is similar to hematopoietic stem cell transplantation (Table).^7,8

Prevention
Acute GVHD following OLT can be prevented by eliminating donor T lymphocytes from the liver before transplantation. However, because the incidence of acute GVHD following OLT is very low, this approach is not routinely taken.²

Conclusion

Acute GVHD following liver transplantation is a rare complication; however, it has high mortality, necessitating further research regarding treatment and prevention. Early recognition and treatment of this condition can improve outcomes. Dermatologists should be familiar with the skin manifestations of acute GVHD following liver transplantation due to the rising number of cases of solid-organ transplantation.

Clinical Pulmonary Medicine

Pulmonary embolism in pregnancy: A diagnostic conundrum

Pulmonary embolism (PE) is the 6th leading cause of maternal mortality in the United States. The clinical signs and symptoms of PE are usually nonspecific and often overlap with the normal physiologic changes of pregnancy. Due to low specificity and sensitivity of D-dimer test, pregnant patients with suspected PE often undergo CT pulmonary angiography (CTPA) and ventilation-perfusion scanning, both of which can cause radiation exposure to mother and fetus.

To answer whether pregnancy-adapted YEARS algorithm (Van der Hulle T et al. Lancet. 2017;390[10091]:289) can be safely used to avoid diagnostic imaging, Artemis Study Investigators prospectively studied three criteria from YEARS algorithm in combination with a D-dimer level (Van der Pol et al. N Engl J Med. 2019;380[12]:1139. The three criteria included clinical signs of deep-vein thrombosis (DVT), hemoptysis, and PE as the most likely diagnosis. PE was considered ruled out when none of the three criteria were present and D-dimer was less than 1000 ng/mL or if one or more of the criteria were met and D-dimer was less than 500 ng/mL. Patients in whom D-dimer was greater than 1000 ng/mL or in those with D-dimer greater than 500 ng/mL and had 1 or more of the YEARS algorithm criteria present, PE could not be ruled out and underwent CTPA. A modification of the criteria was done only for patients who had clinical signs of DVT at baseline. These patients underwent compression ultrasonography and if a clot was found, CTPA was not performed and patients were started on anticoagulation therapy. Those with negative DVT studies were subclassified based on D-dimer levels as the study population above. Patients in whom pulmonary embolism was not ruled out underwent CTPA. Of these 299 patients, 16 (5.4%) were confirmed to have PE at baseline.

In the remaining 195 patients in whom PE was ruled out on the basis of study protocol, a 3-month follow-up diagnosed one patient (0.51%) with VTE. Using pregnancy-adapted YEARS algorithm, CTPA was avoided in 39% of the patients of which 65% were in their first trimester when the radiation exposure can be most harmful to the fetus.

Muhammad Adrish, MD, FCCP
Steering Committee Member

Munish Luthra, MD, FCCP
Steering Committee Member
 

Cardiovascular Medicine and Surgery

Physical examination of low cardiac output in the ICU

Regarding determination of shock etiology, in a small series of patients with systolic blood pressure < 90 mm Hg, physical exam findings of relatively warm skin temperature and rapid capillary refill had 89% sensitivity for vasodilatory shock, and jugular venous pressure ≥8 had 82% sensitivity for cardiogenic etiologies (Vazquez, et al. J Hosp Med. 2010;5[8]:471). Thus, while physical exam findings may inform bedside shock assessment, their accuracy is limited. Critical care physicians should consider additional assessment techniques, such as echocardiography or invasive hemodynamic monitoring, if diagnostic uncertainty persists (Vincent, et al. N Engl J Med. 2013;369[18]:1726).

Benjamin Kenigsberg, MD
Steering Committee Member

Dr. David Bowton and Dr. Steven Hollenberg contributed to the article.
 

Chest Infections

Lung infections in the transplant recipients

Multiple factors contribute to this increased infection risk, including donor lung colonization, disruption of local host defenses, constant contact with environmental pathogens, and heavy immunosuppression (Redmund KF, et al. Proc Am Thorac Soc. 2009;6[1]:94).

The onset of infectious manifestations, from the time of transplantation, is variable, depending on the organism. Based on the time of onset, infections can be categorized into within the first month posttransplant, 1 to 6 months, and beyond 6 months, posttransplant. During the first month, because of allograft colonization, preexisting infections in the recipient, and surgical- and hospital-acquired nosocomial infections are more common. The first 6 months are where the patients are at the highest risk for opportunistic infections. As the immunosuppression is lowered after 6 months, the causative organisms tend to be more common pathogens (Green M. Am J Transplant. 2013;13 [suppl 4]:3-8).

An early, aggressive, empiric antimicrobial therapy initiation and proactive, invasive diagnostic approach with needed testing to identify the potential pathogen, is imperative in these patients. Early bronchoscopy with bronchoalveolar lavage remains the most sensitive test to identify pathogens. Therapy can then be tailored toward the identified pathogen.

As part of the Chest Infections NetWork, we would like to raise awareness of lung infections in unique subgroups, such as lung transplant recipients. Treating infections in such patients requires a high index of suspicion in the setting of an atypical presentation.

Raed Alalawi, MD, FCCP
Steering Committee Member
 

Interprofessional Team

Extracorporeal Membrane Oxygenation (ECMO) in Near Fatal Asthma

Use of early ECMO to permit spontaneous breathing while the circuit accomplishes required ventilation and oxygenation seems more ideal. Avoidance of mechanical ventilation not only prevents complications like barotrauma but also may reduce delirium, malnutrition, and neuromuscular dysfunction. Performing “awake” ECMO has successfully been described for obstructive airway disease (Langer T, et al. Critical Care. 2016;20[1]:150). Factors limiting this approach are the invasive nature of ECMO and the inherent risks of large cannula dislodgement; however, the safety of this has been demonstrated with ambulation of ECMO patients to receive physical therapy (Abrams D, et al. Ann Cardiothorac Surg. 2019;8[1]:44). Alternatively, extracorporeal carbon dioxide removal (ECCO2R) systems utilize smaller catheters to satisfactorily remove CO₂ while oxygen supplementation could be achieved via nasal cannula (Pisani L, et al. Respiratory Care. 2018;63[9]:1174). Incorporation of ECMO in select cases of NFA, especially ECCO2R, should be considered as an early rather than rescue therapy for acute severe asthma refractory to conventional medical therapy.

Robert Baeten, DMSc, PA-C, FCCP
Steering Committee Member

Munish Luthra MD, FCCP
Steering Committee Member
 

Clinical Pulmonary Medicine

Pulmonary embolism in pregnancy: A diagnostic conundrum

Pulmonary embolism (PE) is the 6th leading cause of maternal mortality in the United States. The clinical signs and symptoms of PE are usually nonspecific and often overlap with the normal physiologic changes of pregnancy. Due to low specificity and sensitivity of D-dimer test, pregnant patients with suspected PE often undergo CT pulmonary angiography (CTPA) and ventilation-perfusion scanning, both of which can cause radiation exposure to mother and fetus.

To answer whether pregnancy-adapted YEARS algorithm (Van der Hulle T et al. Lancet. 2017;390[10091]:289) can be safely used to avoid diagnostic imaging, Artemis Study Investigators prospectively studied three criteria from YEARS algorithm in combination with a D-dimer level (Van der Pol et al. N Engl J Med. 2019;380[12]:1139. The three criteria included clinical signs of deep-vein thrombosis (DVT), hemoptysis, and PE as the most likely diagnosis. PE was considered ruled out when none of the three criteria were present and D-dimer was less than 1000 ng/mL or if one or more of the criteria were met and D-dimer was less than 500 ng/mL. Patients in whom D-dimer was greater than 1000 ng/mL or in those with D-dimer greater than 500 ng/mL and had 1 or more of the YEARS algorithm criteria present, PE could not be ruled out and underwent CTPA. A modification of the criteria was done only for patients who had clinical signs of DVT at baseline. These patients underwent compression ultrasonography and if a clot was found, CTPA was not performed and patients were started on anticoagulation therapy. Those with negative DVT studies were subclassified based on D-dimer levels as the study population above. Patients in whom pulmonary embolism was not ruled out underwent CTPA. Of these 299 patients, 16 (5.4%) were confirmed to have PE at baseline.

In the remaining 195 patients in whom PE was ruled out on the basis of study protocol, a 3-month follow-up diagnosed one patient (0.51%) with VTE. Using pregnancy-adapted YEARS algorithm, CTPA was avoided in 39% of the patients of which 65% were in their first trimester when the radiation exposure can be most harmful to the fetus.

Muhammad Adrish, MD, FCCP
Steering Committee Member

Munish Luthra, MD, FCCP
Steering Committee Member
 

Cardiovascular Medicine and Surgery

Physical examination of low cardiac output in the ICU

Regarding determination of shock etiology, in a small series of patients with systolic blood pressure < 90 mm Hg, physical exam findings of relatively warm skin temperature and rapid capillary refill had 89% sensitivity for vasodilatory shock, and jugular venous pressure ≥8 had 82% sensitivity for cardiogenic etiologies (Vazquez, et al. J Hosp Med. 2010;5[8]:471). Thus, while physical exam findings may inform bedside shock assessment, their accuracy is limited. Critical care physicians should consider additional assessment techniques, such as echocardiography or invasive hemodynamic monitoring, if diagnostic uncertainty persists (Vincent, et al. N Engl J Med. 2013;369[18]:1726).

Benjamin Kenigsberg, MD
Steering Committee Member

Dr. David Bowton and Dr. Steven Hollenberg contributed to the article.
 

Chest Infections

Lung infections in the transplant recipients

Multiple factors contribute to this increased infection risk, including donor lung colonization, disruption of local host defenses, constant contact with environmental pathogens, and heavy immunosuppression (Redmund KF, et al. Proc Am Thorac Soc. 2009;6[1]:94).

The onset of infectious manifestations, from the time of transplantation, is variable, depending on the organism. Based on the time of onset, infections can be categorized into within the first month posttransplant, 1 to 6 months, and beyond 6 months, posttransplant. During the first month, because of allograft colonization, preexisting infections in the recipient, and surgical- and hospital-acquired nosocomial infections are more common. The first 6 months are where the patients are at the highest risk for opportunistic infections. As the immunosuppression is lowered after 6 months, the causative organisms tend to be more common pathogens (Green M. Am J Transplant. 2013;13 [suppl 4]:3-8).

An early, aggressive, empiric antimicrobial therapy initiation and proactive, invasive diagnostic approach with needed testing to identify the potential pathogen, is imperative in these patients. Early bronchoscopy with bronchoalveolar lavage remains the most sensitive test to identify pathogens. Therapy can then be tailored toward the identified pathogen.

As part of the Chest Infections NetWork, we would like to raise awareness of lung infections in unique subgroups, such as lung transplant recipients. Treating infections in such patients requires a high index of suspicion in the setting of an atypical presentation.

Raed Alalawi, MD, FCCP
Steering Committee Member
 

Interprofessional Team

Extracorporeal Membrane Oxygenation (ECMO) in Near Fatal Asthma

Use of early ECMO to permit spontaneous breathing while the circuit accomplishes required ventilation and oxygenation seems more ideal. Avoidance of mechanical ventilation not only prevents complications like barotrauma but also may reduce delirium, malnutrition, and neuromuscular dysfunction. Performing “awake” ECMO has successfully been described for obstructive airway disease (Langer T, et al. Critical Care. 2016;20[1]:150). Factors limiting this approach are the invasive nature of ECMO and the inherent risks of large cannula dislodgement; however, the safety of this has been demonstrated with ambulation of ECMO patients to receive physical therapy (Abrams D, et al. Ann Cardiothorac Surg. 2019;8[1]:44). Alternatively, extracorporeal carbon dioxide removal (ECCO2R) systems utilize smaller catheters to satisfactorily remove CO₂ while oxygen supplementation could be achieved via nasal cannula (Pisani L, et al. Respiratory Care. 2018;63[9]:1174). Incorporation of ECMO in select cases of NFA, especially ECCO2R, should be considered as an early rather than rescue therapy for acute severe asthma refractory to conventional medical therapy.

Robert Baeten, DMSc, PA-C, FCCP
Steering Committee Member

Munish Luthra MD, FCCP
Steering Committee Member
 

Clinical Pulmonary Medicine

Pulmonary embolism in pregnancy: A diagnostic conundrum

Pulmonary embolism (PE) is the 6th leading cause of maternal mortality in the United States. The clinical signs and symptoms of PE are usually nonspecific and often overlap with the normal physiologic changes of pregnancy. Due to low specificity and sensitivity of D-dimer test, pregnant patients with suspected PE often undergo CT pulmonary angiography (CTPA) and ventilation-perfusion scanning, both of which can cause radiation exposure to mother and fetus.

To answer whether pregnancy-adapted YEARS algorithm (Van der Hulle T et al. Lancet. 2017;390[10091]:289) can be safely used to avoid diagnostic imaging, Artemis Study Investigators prospectively studied three criteria from YEARS algorithm in combination with a D-dimer level (Van der Pol et al. N Engl J Med. 2019;380[12]:1139. The three criteria included clinical signs of deep-vein thrombosis (DVT), hemoptysis, and PE as the most likely diagnosis. PE was considered ruled out when none of the three criteria were present and D-dimer was less than 1000 ng/mL or if one or more of the criteria were met and D-dimer was less than 500 ng/mL. Patients in whom D-dimer was greater than 1000 ng/mL or in those with D-dimer greater than 500 ng/mL and had 1 or more of the YEARS algorithm criteria present, PE could not be ruled out and underwent CTPA. A modification of the criteria was done only for patients who had clinical signs of DVT at baseline. These patients underwent compression ultrasonography and if a clot was found, CTPA was not performed and patients were started on anticoagulation therapy. Those with negative DVT studies were subclassified based on D-dimer levels as the study population above. Patients in whom pulmonary embolism was not ruled out underwent CTPA. Of these 299 patients, 16 (5.4%) were confirmed to have PE at baseline.

In the remaining 195 patients in whom PE was ruled out on the basis of study protocol, a 3-month follow-up diagnosed one patient (0.51%) with VTE. Using pregnancy-adapted YEARS algorithm, CTPA was avoided in 39% of the patients of which 65% were in their first trimester when the radiation exposure can be most harmful to the fetus.

Muhammad Adrish, MD, FCCP
Steering Committee Member

Munish Luthra, MD, FCCP
Steering Committee Member
 

Cardiovascular Medicine and Surgery

Physical examination of low cardiac output in the ICU

Regarding determination of shock etiology, in a small series of patients with systolic blood pressure < 90 mm Hg, physical exam findings of relatively warm skin temperature and rapid capillary refill had 89% sensitivity for vasodilatory shock, and jugular venous pressure ≥8 had 82% sensitivity for cardiogenic etiologies (Vazquez, et al. J Hosp Med. 2010;5[8]:471). Thus, while physical exam findings may inform bedside shock assessment, their accuracy is limited. Critical care physicians should consider additional assessment techniques, such as echocardiography or invasive hemodynamic monitoring, if diagnostic uncertainty persists (Vincent, et al. N Engl J Med. 2013;369[18]:1726).

Benjamin Kenigsberg, MD
Steering Committee Member

Dr. David Bowton and Dr. Steven Hollenberg contributed to the article.
 

Chest Infections

Lung infections in the transplant recipients

Multiple factors contribute to this increased infection risk, including donor lung colonization, disruption of local host defenses, constant contact with environmental pathogens, and heavy immunosuppression (Redmund KF, et al. Proc Am Thorac Soc. 2009;6[1]:94).

The onset of infectious manifestations, from the time of transplantation, is variable, depending on the organism. Based on the time of onset, infections can be categorized into within the first month posttransplant, 1 to 6 months, and beyond 6 months, posttransplant. During the first month, because of allograft colonization, preexisting infections in the recipient, and surgical- and hospital-acquired nosocomial infections are more common. The first 6 months are where the patients are at the highest risk for opportunistic infections. As the immunosuppression is lowered after 6 months, the causative organisms tend to be more common pathogens (Green M. Am J Transplant. 2013;13 [suppl 4]:3-8).

An early, aggressive, empiric antimicrobial therapy initiation and proactive, invasive diagnostic approach with needed testing to identify the potential pathogen, is imperative in these patients. Early bronchoscopy with bronchoalveolar lavage remains the most sensitive test to identify pathogens. Therapy can then be tailored toward the identified pathogen.

As part of the Chest Infections NetWork, we would like to raise awareness of lung infections in unique subgroups, such as lung transplant recipients. Treating infections in such patients requires a high index of suspicion in the setting of an atypical presentation.

Raed Alalawi, MD, FCCP
Steering Committee Member
 

Interprofessional Team

Extracorporeal Membrane Oxygenation (ECMO) in Near Fatal Asthma

Use of early ECMO to permit spontaneous breathing while the circuit accomplishes required ventilation and oxygenation seems more ideal. Avoidance of mechanical ventilation not only prevents complications like barotrauma but also may reduce delirium, malnutrition, and neuromuscular dysfunction. Performing “awake” ECMO has successfully been described for obstructive airway disease (Langer T, et al. Critical Care. 2016;20[1]:150). Factors limiting this approach are the invasive nature of ECMO and the inherent risks of large cannula dislodgement; however, the safety of this has been demonstrated with ambulation of ECMO patients to receive physical therapy (Abrams D, et al. Ann Cardiothorac Surg. 2019;8[1]:44). Alternatively, extracorporeal carbon dioxide removal (ECCO2R) systems utilize smaller catheters to satisfactorily remove CO₂ while oxygen supplementation could be achieved via nasal cannula (Pisani L, et al. Respiratory Care. 2018;63[9]:1174). Incorporation of ECMO in select cases of NFA, especially ECCO2R, should be considered as an early rather than rescue therapy for acute severe asthma refractory to conventional medical therapy.

Robert Baeten, DMSc, PA-C, FCCP
Steering Committee Member

Munish Luthra MD, FCCP
Steering Committee Member
 

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

[email protected]

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

[email protected]

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

[email protected]

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.

SAN DIEGO – For patients with acute gastroenteritis, multiplex polymerase chain reaction (PCR)–based gastrointestinal pathogen testing was associated with lower resource utilization and less antibiotic prescribing, compared with conventional stool culture methods. However, antibiotics were still prescribed for more than one in three patients tested by any method.

“A positive test by any modality did result in decreased utilization of endoscopy, radiology, and antibiotic prescribing, but this effect appeared to be much greater for the GI PCR assay,” said Jordan Axelrad, MD, speaking at the annual Digestive Disease Week.

“Overall, patients who received GI PCR were 12% less likely to undergo endoscopy, 7% less likely to undergo abdominal radiography, and 11% less likely to be prescribed any antibiotic,” compared with patients who were tested by conventional stool culture, said Dr. Axelrad, a gastroenterologist at New York University.

In a cross-sectional study, Dr. Axelrad and his coauthors looked at patients who underwent stool testing for the 26 months before (n = 5,986) and after (n = 9,402) March 2015, when Dr. Axelrad’s home institution switched from conventional stool culture to the GI PCR panel. For the earlier time period, the investigators included patients who received stool culture both with and without an ova and parasites exam, as well as those who underwent enzyme-linked immunosorbent assay viral testing for rotavirus and adenovirus.

Patient demographic data were included as study variables; additionally, the study tracked utilization of endoscopy, abdominal, or other radiology studies, and ED visits for 30 days after testing. They also included any antibiotic prescribing within the 14 days post testing.

Roughly one-third of patients were tested as outpatients, 1 in 10 in the ED, and the remainder as inpatients. Patient age was a mean 46.7 years for the culture group, and 45.5 years for the GI PCR group.

The multiplex PCR test used in the study tested for 12 gastrointestinal pathogenic bacteria, 4 parasites, and 5 viruses.

As expected, PCR testing yielded a higher positive test rate than conventional stool testing, even when EIA tests were included (29.2% vs. 4.1%). In the 2,746 patients with a positive GI PCR test, a total of 3,804 pathogens were identified. Adenovirus accounted for 39% of these positive results. Positive bacterial results were seen in about 65.0% of the positive subgroup, with Escherichia coli subtypes seen in 51.7% of the positive tests.

Overall, positive results for viruses, bacteria, and multiple pathogens were more likely with GI PCR testing, compared with conventional testing (P = .001 for all). Parasites accounted for only 8.2% of the positive PCR test results, but this was significantly more than the 3.7% seen with conventional testing (P = .011).

At the 14-day mark post testing, “Patients who underwent a GI panel were less likely to be prescribed any antibiotic. But overall, antibiotics were fairly common in both groups,” said Dr. Axelrad, noting that 41% of patients who underwent stool culture received an antibiotic by 14 days, compared with 36% for patients who underwent a GI PCR panel (P = .001).

By the end of 30 days, most patients in each group had not received an endoscopic procedure, with significantly more procedure-free patients in the PCR group (91.6% vs. 90.4%; P = .008).

Against a backdrop of slightly higher overall radiology utilization in the PCR group – potentially attributable to practice trends over time – abdominal radiology was less likely for these patients than for the culture group (11.4% vs. 12.8%; P = .011).

The 30-day ED visit rate was low and similar between groups (11.4% for PCR vs. 12.8% for culture; P = .116).

The much quicker turnaround for the GI PCR panel didn’t translate into a shorter length of stay, though: Inpatient length of stay was a median 5 days in both groups.

“We feel that the outcomes that we noted were likely due to the increased sensitivity and specificity” of the PCR-based testing, said Dr. Axelrad. “Obviously, if you have more pathogen-positive findings, you may be less likely to order extensive testing. And if you’ve identified something like norovirus, you may feel reassured, and not order further testing.”

Dr. Axelrad pointed out that his institution’s overall PCR positivity rates were lower than the 70% rates some other studies have reported. “We feel that, given our large sample size, our results may more accurately reflect clinical practice, and perhaps that lower positivity rate may reflect increased use of this test in an inpatient setting,” he said. “We’re looking at that.”

Study limitations included the retrospective nature of the study. “Also, as we all know, PCR testing fails to discriminate between active infection and asymptomatic colonization,” raising questions about whether a positive PCR test really indicates true infection, noted Dr. Axelrad.

“Coupled with a high-sensitivity rapid turnaround, there’s the potential to reduce costs, but the cost-effectiveness of these assays has not been fully determined. There are several studies looking at this,” with results still to come, he said.

The notable reduction in antibiotic prescribing for those patients who received PCR-based testing means that GI PCR panels could be a useful tool to promote antibiotic stewardship, though Dr. Axelrad also noted that “antibiotics were still used in about a third of all patients.”

Dr. Axelrad reported no outside sources of funding. He has performed consulting services for and received research funding from BioFire, which manufactured the GI PCR assay used in the study, but BioFire did not fund this research.

[email protected]

SOURCE: Axelrad J et al. DDW 2019, Presentation 978.

SAN DIEGO – For patients with acute gastroenteritis, multiplex polymerase chain reaction (PCR)–based gastrointestinal pathogen testing was associated with lower resource utilization and less antibiotic prescribing, compared with conventional stool culture methods. However, antibiotics were still prescribed for more than one in three patients tested by any method.

“A positive test by any modality did result in decreased utilization of endoscopy, radiology, and antibiotic prescribing, but this effect appeared to be much greater for the GI PCR assay,” said Jordan Axelrad, MD, speaking at the annual Digestive Disease Week.

“Overall, patients who received GI PCR were 12% less likely to undergo endoscopy, 7% less likely to undergo abdominal radiography, and 11% less likely to be prescribed any antibiotic,” compared with patients who were tested by conventional stool culture, said Dr. Axelrad, a gastroenterologist at New York University.

In a cross-sectional study, Dr. Axelrad and his coauthors looked at patients who underwent stool testing for the 26 months before (n = 5,986) and after (n = 9,402) March 2015, when Dr. Axelrad’s home institution switched from conventional stool culture to the GI PCR panel. For the earlier time period, the investigators included patients who received stool culture both with and without an ova and parasites exam, as well as those who underwent enzyme-linked immunosorbent assay viral testing for rotavirus and adenovirus.

Patient demographic data were included as study variables; additionally, the study tracked utilization of endoscopy, abdominal, or other radiology studies, and ED visits for 30 days after testing. They also included any antibiotic prescribing within the 14 days post testing.

Roughly one-third of patients were tested as outpatients, 1 in 10 in the ED, and the remainder as inpatients. Patient age was a mean 46.7 years for the culture group, and 45.5 years for the GI PCR group.

The multiplex PCR test used in the study tested for 12 gastrointestinal pathogenic bacteria, 4 parasites, and 5 viruses.

As expected, PCR testing yielded a higher positive test rate than conventional stool testing, even when EIA tests were included (29.2% vs. 4.1%). In the 2,746 patients with a positive GI PCR test, a total of 3,804 pathogens were identified. Adenovirus accounted for 39% of these positive results. Positive bacterial results were seen in about 65.0% of the positive subgroup, with Escherichia coli subtypes seen in 51.7% of the positive tests.

Overall, positive results for viruses, bacteria, and multiple pathogens were more likely with GI PCR testing, compared with conventional testing (P = .001 for all). Parasites accounted for only 8.2% of the positive PCR test results, but this was significantly more than the 3.7% seen with conventional testing (P = .011).

At the 14-day mark post testing, “Patients who underwent a GI panel were less likely to be prescribed any antibiotic. But overall, antibiotics were fairly common in both groups,” said Dr. Axelrad, noting that 41% of patients who underwent stool culture received an antibiotic by 14 days, compared with 36% for patients who underwent a GI PCR panel (P = .001).

By the end of 30 days, most patients in each group had not received an endoscopic procedure, with significantly more procedure-free patients in the PCR group (91.6% vs. 90.4%; P = .008).

Against a backdrop of slightly higher overall radiology utilization in the PCR group – potentially attributable to practice trends over time – abdominal radiology was less likely for these patients than for the culture group (11.4% vs. 12.8%; P = .011).

The 30-day ED visit rate was low and similar between groups (11.4% for PCR vs. 12.8% for culture; P = .116).

The much quicker turnaround for the GI PCR panel didn’t translate into a shorter length of stay, though: Inpatient length of stay was a median 5 days in both groups.

“We feel that the outcomes that we noted were likely due to the increased sensitivity and specificity” of the PCR-based testing, said Dr. Axelrad. “Obviously, if you have more pathogen-positive findings, you may be less likely to order extensive testing. And if you’ve identified something like norovirus, you may feel reassured, and not order further testing.”

Dr. Axelrad pointed out that his institution’s overall PCR positivity rates were lower than the 70% rates some other studies have reported. “We feel that, given our large sample size, our results may more accurately reflect clinical practice, and perhaps that lower positivity rate may reflect increased use of this test in an inpatient setting,” he said. “We’re looking at that.”

Study limitations included the retrospective nature of the study. “Also, as we all know, PCR testing fails to discriminate between active infection and asymptomatic colonization,” raising questions about whether a positive PCR test really indicates true infection, noted Dr. Axelrad.

“Coupled with a high-sensitivity rapid turnaround, there’s the potential to reduce costs, but the cost-effectiveness of these assays has not been fully determined. There are several studies looking at this,” with results still to come, he said.

The notable reduction in antibiotic prescribing for those patients who received PCR-based testing means that GI PCR panels could be a useful tool to promote antibiotic stewardship, though Dr. Axelrad also noted that “antibiotics were still used in about a third of all patients.”

Dr. Axelrad reported no outside sources of funding. He has performed consulting services for and received research funding from BioFire, which manufactured the GI PCR assay used in the study, but BioFire did not fund this research.

[email protected]

SOURCE: Axelrad J et al. DDW 2019, Presentation 978.

SAN DIEGO – For patients with acute gastroenteritis, multiplex polymerase chain reaction (PCR)–based gastrointestinal pathogen testing was associated with lower resource utilization and less antibiotic prescribing, compared with conventional stool culture methods. However, antibiotics were still prescribed for more than one in three patients tested by any method.

“A positive test by any modality did result in decreased utilization of endoscopy, radiology, and antibiotic prescribing, but this effect appeared to be much greater for the GI PCR assay,” said Jordan Axelrad, MD, speaking at the annual Digestive Disease Week.

“Overall, patients who received GI PCR were 12% less likely to undergo endoscopy, 7% less likely to undergo abdominal radiography, and 11% less likely to be prescribed any antibiotic,” compared with patients who were tested by conventional stool culture, said Dr. Axelrad, a gastroenterologist at New York University.

In a cross-sectional study, Dr. Axelrad and his coauthors looked at patients who underwent stool testing for the 26 months before (n = 5,986) and after (n = 9,402) March 2015, when Dr. Axelrad’s home institution switched from conventional stool culture to the GI PCR panel. For the earlier time period, the investigators included patients who received stool culture both with and without an ova and parasites exam, as well as those who underwent enzyme-linked immunosorbent assay viral testing for rotavirus and adenovirus.

Patient demographic data were included as study variables; additionally, the study tracked utilization of endoscopy, abdominal, or other radiology studies, and ED visits for 30 days after testing. They also included any antibiotic prescribing within the 14 days post testing.

Roughly one-third of patients were tested as outpatients, 1 in 10 in the ED, and the remainder as inpatients. Patient age was a mean 46.7 years for the culture group, and 45.5 years for the GI PCR group.

The multiplex PCR test used in the study tested for 12 gastrointestinal pathogenic bacteria, 4 parasites, and 5 viruses.

As expected, PCR testing yielded a higher positive test rate than conventional stool testing, even when EIA tests were included (29.2% vs. 4.1%). In the 2,746 patients with a positive GI PCR test, a total of 3,804 pathogens were identified. Adenovirus accounted for 39% of these positive results. Positive bacterial results were seen in about 65.0% of the positive subgroup, with Escherichia coli subtypes seen in 51.7% of the positive tests.

Overall, positive results for viruses, bacteria, and multiple pathogens were more likely with GI PCR testing, compared with conventional testing (P = .001 for all). Parasites accounted for only 8.2% of the positive PCR test results, but this was significantly more than the 3.7% seen with conventional testing (P = .011).

At the 14-day mark post testing, “Patients who underwent a GI panel were less likely to be prescribed any antibiotic. But overall, antibiotics were fairly common in both groups,” said Dr. Axelrad, noting that 41% of patients who underwent stool culture received an antibiotic by 14 days, compared with 36% for patients who underwent a GI PCR panel (P = .001).

By the end of 30 days, most patients in each group had not received an endoscopic procedure, with significantly more procedure-free patients in the PCR group (91.6% vs. 90.4%; P = .008).

Against a backdrop of slightly higher overall radiology utilization in the PCR group – potentially attributable to practice trends over time – abdominal radiology was less likely for these patients than for the culture group (11.4% vs. 12.8%; P = .011).

The 30-day ED visit rate was low and similar between groups (11.4% for PCR vs. 12.8% for culture; P = .116).

The much quicker turnaround for the GI PCR panel didn’t translate into a shorter length of stay, though: Inpatient length of stay was a median 5 days in both groups.

“We feel that the outcomes that we noted were likely due to the increased sensitivity and specificity” of the PCR-based testing, said Dr. Axelrad. “Obviously, if you have more pathogen-positive findings, you may be less likely to order extensive testing. And if you’ve identified something like norovirus, you may feel reassured, and not order further testing.”

Dr. Axelrad pointed out that his institution’s overall PCR positivity rates were lower than the 70% rates some other studies have reported. “We feel that, given our large sample size, our results may more accurately reflect clinical practice, and perhaps that lower positivity rate may reflect increased use of this test in an inpatient setting,” he said. “We’re looking at that.”

Study limitations included the retrospective nature of the study. “Also, as we all know, PCR testing fails to discriminate between active infection and asymptomatic colonization,” raising questions about whether a positive PCR test really indicates true infection, noted Dr. Axelrad.

“Coupled with a high-sensitivity rapid turnaround, there’s the potential to reduce costs, but the cost-effectiveness of these assays has not been fully determined. There are several studies looking at this,” with results still to come, he said.

The notable reduction in antibiotic prescribing for those patients who received PCR-based testing means that GI PCR panels could be a useful tool to promote antibiotic stewardship, though Dr. Axelrad also noted that “antibiotics were still used in about a third of all patients.”

Dr. Axelrad reported no outside sources of funding. He has performed consulting services for and received research funding from BioFire, which manufactured the GI PCR assay used in the study, but BioFire did not fund this research.

[email protected]

SOURCE: Axelrad J et al. DDW 2019, Presentation 978.

Pre-exposure prophylaxis (PrEP) plus effective antiretroviral therapy should be offered to people at high risk of HIV acquisition, according to a new recommendation from the U.S. Preventive Services Task Force (USPSTF).

“The USPSTF concludes with high certainty that the net benefit of the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection is substantial,” wrote first author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the USPSTF. The recommendation was published in JAMA.

In various at-risk groups – including men who have sex with men, people at risk through heterosexual contact, and people who inject drugs – the USPSTF recommends a Food and Drug Adminstration–approved, once-daily oral treatment with combined tenofovir disoproxil fumarate and emtricitabine. In addition, tenofovir disoproxil fumarate alone can be considered an alternative regimen for high-risk heterosexually active men and women and people who inject drugs.

This recommendation was developed after a systematic review of PrEP’s effects on HIV, adherence to the treatment, and accuracy in identifying potential treatment candidates. “The findings of this review are generally consistent with those from other recent meta-analyses that found PrEP to be effective at reducing risk of HIV infection and found greater effectiveness in trials reporting higher adherence,” wrote Roger Chou, MD, of Oregon Health & Science University in Portland and coauthors. Their study was also published in JAMA.

To comprehensively assess PrEP and thus inform the USPSTF’s HIV prevention recommendations, the researchers reviewed criteria-meeting studies on oral PrEP with tenofovir disoproxil fumarate/emtricitabine or tenofovir disoproxil fumarate monotherapy; on the diagnostic accuracy of instruments to predict HIV infection; and on PrEP adherence. The final analysis included 14 randomized clinical trials, 8 observational studies, and 7 studies of diagnostic accuracy.

In 11 of the trials, PrEP was associated with reduced risk of HIV infection versus placebo or no PrEP (relative risk, 0.46; 95% confidence interval, 0.33-0.66). In 6 trials with adherence 70% or greater, the relative risk was 0.27 (95% CI, 0.19-0.39). In 7 studies on risk assessment tools for HIV infection, the instruments had moderate discrimination, though several of the studies had methodological shortcomings. As for serious adverse events, an analysis of 12 trials found no significant difference between PrEP and placebo (RR, 0.93; 95% CI, 0.77-1.12).

Dr. Chou and coauthors noted their study’s limitations, including analyzing English-language articles only and the random-effects model used to pool studies potentially returning narrow CIs. They did note, however, that the “analyses were repeated using the profile likelihood method,” which produced similar findings.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in meetings. The study was funded by the Department of Health and Human Services. One of the authors reported receiving grants from the National Institutes of Health/National Institute on Drug Abuse and serving as principal investigator of NIH-funded clinical trials that received donated drugs from two pharmaceutical companies. No other conflicts of interest were reported.

SOURCE: Owens DK et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.6390; Chou R et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.2591.

Pre-exposure prophylaxis (PrEP) plus effective antiretroviral therapy should be offered to people at high risk of HIV acquisition, according to a new recommendation from the U.S. Preventive Services Task Force (USPSTF).

“The USPSTF concludes with high certainty that the net benefit of the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection is substantial,” wrote first author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the USPSTF. The recommendation was published in JAMA.

In various at-risk groups – including men who have sex with men, people at risk through heterosexual contact, and people who inject drugs – the USPSTF recommends a Food and Drug Adminstration–approved, once-daily oral treatment with combined tenofovir disoproxil fumarate and emtricitabine. In addition, tenofovir disoproxil fumarate alone can be considered an alternative regimen for high-risk heterosexually active men and women and people who inject drugs.

This recommendation was developed after a systematic review of PrEP’s effects on HIV, adherence to the treatment, and accuracy in identifying potential treatment candidates. “The findings of this review are generally consistent with those from other recent meta-analyses that found PrEP to be effective at reducing risk of HIV infection and found greater effectiveness in trials reporting higher adherence,” wrote Roger Chou, MD, of Oregon Health & Science University in Portland and coauthors. Their study was also published in JAMA.

To comprehensively assess PrEP and thus inform the USPSTF’s HIV prevention recommendations, the researchers reviewed criteria-meeting studies on oral PrEP with tenofovir disoproxil fumarate/emtricitabine or tenofovir disoproxil fumarate monotherapy; on the diagnostic accuracy of instruments to predict HIV infection; and on PrEP adherence. The final analysis included 14 randomized clinical trials, 8 observational studies, and 7 studies of diagnostic accuracy.

In 11 of the trials, PrEP was associated with reduced risk of HIV infection versus placebo or no PrEP (relative risk, 0.46; 95% confidence interval, 0.33-0.66). In 6 trials with adherence 70% or greater, the relative risk was 0.27 (95% CI, 0.19-0.39). In 7 studies on risk assessment tools for HIV infection, the instruments had moderate discrimination, though several of the studies had methodological shortcomings. As for serious adverse events, an analysis of 12 trials found no significant difference between PrEP and placebo (RR, 0.93; 95% CI, 0.77-1.12).

Dr. Chou and coauthors noted their study’s limitations, including analyzing English-language articles only and the random-effects model used to pool studies potentially returning narrow CIs. They did note, however, that the “analyses were repeated using the profile likelihood method,” which produced similar findings.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in meetings. The study was funded by the Department of Health and Human Services. One of the authors reported receiving grants from the National Institutes of Health/National Institute on Drug Abuse and serving as principal investigator of NIH-funded clinical trials that received donated drugs from two pharmaceutical companies. No other conflicts of interest were reported.

SOURCE: Owens DK et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.6390; Chou R et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.2591.

Pre-exposure prophylaxis (PrEP) plus effective antiretroviral therapy should be offered to people at high risk of HIV acquisition, according to a new recommendation from the U.S. Preventive Services Task Force (USPSTF).

“The USPSTF concludes with high certainty that the net benefit of the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection is substantial,” wrote first author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the USPSTF. The recommendation was published in JAMA.

In various at-risk groups – including men who have sex with men, people at risk through heterosexual contact, and people who inject drugs – the USPSTF recommends a Food and Drug Adminstration–approved, once-daily oral treatment with combined tenofovir disoproxil fumarate and emtricitabine. In addition, tenofovir disoproxil fumarate alone can be considered an alternative regimen for high-risk heterosexually active men and women and people who inject drugs.

This recommendation was developed after a systematic review of PrEP’s effects on HIV, adherence to the treatment, and accuracy in identifying potential treatment candidates. “The findings of this review are generally consistent with those from other recent meta-analyses that found PrEP to be effective at reducing risk of HIV infection and found greater effectiveness in trials reporting higher adherence,” wrote Roger Chou, MD, of Oregon Health & Science University in Portland and coauthors. Their study was also published in JAMA.

To comprehensively assess PrEP and thus inform the USPSTF’s HIV prevention recommendations, the researchers reviewed criteria-meeting studies on oral PrEP with tenofovir disoproxil fumarate/emtricitabine or tenofovir disoproxil fumarate monotherapy; on the diagnostic accuracy of instruments to predict HIV infection; and on PrEP adherence. The final analysis included 14 randomized clinical trials, 8 observational studies, and 7 studies of diagnostic accuracy.

In 11 of the trials, PrEP was associated with reduced risk of HIV infection versus placebo or no PrEP (relative risk, 0.46; 95% confidence interval, 0.33-0.66). In 6 trials with adherence 70% or greater, the relative risk was 0.27 (95% CI, 0.19-0.39). In 7 studies on risk assessment tools for HIV infection, the instruments had moderate discrimination, though several of the studies had methodological shortcomings. As for serious adverse events, an analysis of 12 trials found no significant difference between PrEP and placebo (RR, 0.93; 95% CI, 0.77-1.12).

Dr. Chou and coauthors noted their study’s limitations, including analyzing English-language articles only and the random-effects model used to pool studies potentially returning narrow CIs. They did note, however, that the “analyses were repeated using the profile likelihood method,” which produced similar findings.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in meetings. The study was funded by the Department of Health and Human Services. One of the authors reported receiving grants from the National Institutes of Health/National Institute on Drug Abuse and serving as principal investigator of NIH-funded clinical trials that received donated drugs from two pharmaceutical companies. No other conflicts of interest were reported.

SOURCE: Owens DK et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.6390; Chou R et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.2591.

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.