Clinical question: What is the association between exposure to statin medications and histologically confirmed idiopathic inflammatory myositis?

Background: More than 200 million people worldwide use statin therapy, mostly for cardiovascular risk reduction. There is mounting evidence of an infrequent side effect known as idiopathic inflammatory myositis (IIM), that requires immunosuppressive therapy rather than just discontinuation of the medication. While there is a recently described association of statin use with an immune-mediated necrotizing myositis through the formation of an autoantibody against HMG-CoA Reductase, this epidemiological study aimed to look at the incidence of statin use against all confirmed cases of IIM.

Study design: Retrospective, population-based, case-control study.

Setting: Northwest Adelaide Health Study in Adelaide, Australia.

Synopsis: A retrospective, population-based, case-control study was conducted that compared the incidence of histologically confirmed IIM identified from the South Australian Myositis Database in patients 40 years or older with known statin exposure (n = 221) against population-based controls obtained from the North West Adelaide Health Study. The unadjusted and adjusted odds ratios and 95% confidence intervals were calculated using the conditional logistic regression analysis for the risk of statin exposure associated with IIM. There was an almost twofold (79%) increased likelihood of statin exposure in patients with IIM by comparison with controls (adjusted OR, 1.79; 95% CI, 1.23-2.60; P = .001). This study’s results indicate that patients with histologically confirmed IIM had a significantly increased likelihood of statin exposure, compared with population-based matched controls. Results were similar even when excluding necrotizing myositis, which already has a known association with statin use, which suggests that statin use could be associated with all types of IIM.

Bottom line: There was a statistically significant association between statin use and the incidence of idiopathic inflammatory myositis, which suggests that this condition is a potential serious side effect of statin therapy.

Citation: Caughey GE et al. Association of statin exposure with histologically confirmed idiopathic inflammatory myositis in an Australian population. JAMA Intern Med. 2018 Jul 30. doi: 10.1001/jamainternmed.2018.2859.

Dr. Nave is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: What is the association between exposure to statin medications and histologically confirmed idiopathic inflammatory myositis?

Background: More than 200 million people worldwide use statin therapy, mostly for cardiovascular risk reduction. There is mounting evidence of an infrequent side effect known as idiopathic inflammatory myositis (IIM), that requires immunosuppressive therapy rather than just discontinuation of the medication. While there is a recently described association of statin use with an immune-mediated necrotizing myositis through the formation of an autoantibody against HMG-CoA Reductase, this epidemiological study aimed to look at the incidence of statin use against all confirmed cases of IIM.

Study design: Retrospective, population-based, case-control study.

Setting: Northwest Adelaide Health Study in Adelaide, Australia.

Synopsis: A retrospective, population-based, case-control study was conducted that compared the incidence of histologically confirmed IIM identified from the South Australian Myositis Database in patients 40 years or older with known statin exposure (n = 221) against population-based controls obtained from the North West Adelaide Health Study. The unadjusted and adjusted odds ratios and 95% confidence intervals were calculated using the conditional logistic regression analysis for the risk of statin exposure associated with IIM. There was an almost twofold (79%) increased likelihood of statin exposure in patients with IIM by comparison with controls (adjusted OR, 1.79; 95% CI, 1.23-2.60; P = .001). This study’s results indicate that patients with histologically confirmed IIM had a significantly increased likelihood of statin exposure, compared with population-based matched controls. Results were similar even when excluding necrotizing myositis, which already has a known association with statin use, which suggests that statin use could be associated with all types of IIM.

Bottom line: There was a statistically significant association between statin use and the incidence of idiopathic inflammatory myositis, which suggests that this condition is a potential serious side effect of statin therapy.

Citation: Caughey GE et al. Association of statin exposure with histologically confirmed idiopathic inflammatory myositis in an Australian population. JAMA Intern Med. 2018 Jul 30. doi: 10.1001/jamainternmed.2018.2859.

Dr. Nave is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Clinical question: What is the association between exposure to statin medications and histologically confirmed idiopathic inflammatory myositis?

Background: More than 200 million people worldwide use statin therapy, mostly for cardiovascular risk reduction. There is mounting evidence of an infrequent side effect known as idiopathic inflammatory myositis (IIM), that requires immunosuppressive therapy rather than just discontinuation of the medication. While there is a recently described association of statin use with an immune-mediated necrotizing myositis through the formation of an autoantibody against HMG-CoA Reductase, this epidemiological study aimed to look at the incidence of statin use against all confirmed cases of IIM.

Study design: Retrospective, population-based, case-control study.

Setting: Northwest Adelaide Health Study in Adelaide, Australia.

Synopsis: A retrospective, population-based, case-control study was conducted that compared the incidence of histologically confirmed IIM identified from the South Australian Myositis Database in patients 40 years or older with known statin exposure (n = 221) against population-based controls obtained from the North West Adelaide Health Study. The unadjusted and adjusted odds ratios and 95% confidence intervals were calculated using the conditional logistic regression analysis for the risk of statin exposure associated with IIM. There was an almost twofold (79%) increased likelihood of statin exposure in patients with IIM by comparison with controls (adjusted OR, 1.79; 95% CI, 1.23-2.60; P = .001). This study’s results indicate that patients with histologically confirmed IIM had a significantly increased likelihood of statin exposure, compared with population-based matched controls. Results were similar even when excluding necrotizing myositis, which already has a known association with statin use, which suggests that statin use could be associated with all types of IIM.

Bottom line: There was a statistically significant association between statin use and the incidence of idiopathic inflammatory myositis, which suggests that this condition is a potential serious side effect of statin therapy.

Citation: Caughey GE et al. Association of statin exposure with histologically confirmed idiopathic inflammatory myositis in an Australian population. JAMA Intern Med. 2018 Jul 30. doi: 10.1001/jamainternmed.2018.2859.

Dr. Nave is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

Hematopoietic stem cell transplantation (HSCT) is widely used in the economically developed world to treat a variety of hematologic malignancies as well as nonmalignant diseases and solid tumors. An estimated 17,900 HSCTs were performed in 2011, and survival rates continue to increase.¹ Pulmonary complications post HSCT are common, with rates ranging from 40% to 60%, and are associated with increased morbidity and mortality.²

Clinical diagnosis of pulmonary complications in the HSCT population has been aided by a previously well-defined chronology of the most common diseases.³ Historically, early pulmonary complications were defined as pulmonary complications occurring within 100 days of HSCT (corresponding to the acute graft-versus-host disease [GVHD] period). Late pulmonary complications are those that occur thereafter. This timeline, however, is now more variable given the increasing indications for HSCT, the use of reduced-intensity conditioning strategies, and varied individual immune reconstitution. This article discusses the management of early post-HSCT pulmonary complications; late post-HSCT pulmonary complications will be discussed in a separate follow-up article.

Transplant Basics

The development of pulmonary complications is affected by many factors associated with the transplant. Autologous transplantation involves the collection of a patient’s own stem cells, appropriate storage and processing, and re-implantation after induction therapy. During induction therapy, the patient undergoes high-dose chemotherapy or radiation therapy that ablates the bone marrow. The stem cells are then transfused back into the patient to repopulate the bone marrow. Allogeneic transplants involve the collection of stem cells from a donor. Donors are matched as closely as possible to the recipient’s histocompatibility antigen (HLA) haplotypes to prevent graft failure and rejection. The donor can be related or unrelated to the recipient. If there is not a possibility of a related match (from a sibling), then a national search is undertaken to look for a match through the National Marrow Donor Program. There are fewer transplant reactions and occurrences of GVHD if the major HLAs of the donor and recipient match. Table 1 reviews basic definitions pertaining to HSCT.

How the cells for transplantation are obtained is also an important factor in the rate of complications. There are 3 main sources: peripheral blood, bone marrow, and umbilical cord. Peripheral stem cell harvesting involves exposing the donor to granulocyte-colony stimulating factor (gCSF), which increases peripheral circulation of stem cells. These cells are then collected and infused into the recipient after the recipient has completed an induction regimen involving chemotherapy and/or radiation, depending on the protocol. This procedure is called peripheral blood stem cell transplant (PBSCT). Stem cells can also be directly harvested from bone marrow cells, which are collected from repeated aspiration of bone marrow from the posterior iliac crest.⁴ This technique is most common in children, whereas in adults peripheral blood stem cells are the most common source. Overall mortality does not differ based on the source of the stem cells. It is postulated that GVHD may be more common in patients undergoing PBSCT, but the graft failure rate may be lower.⁵

The third option is umbilical cord blood (UCB) as the source of stem cells. This involves the collection of umbilical cord blood that is prepared and frozen after birth. It has a smaller volume of cells, and although fewer cells are needed when using UCB, 2 separate donors may be required for a single adult recipient. The engraftment of the stem cells is slower and infections in the post-transplant period are more common. Prior reports indicate GVHD rates may be lower.⁴ While the use of UCB is not common in adults, the incidence has doubled over the past decade, increasing from 3% to 6%.

The conditioning regimen can influence pulmonary complications. Traditionally, an ablative transplant involves high-dose chemotherapy or radiation to eradicate the recipient’s bone marrow. This regimen can lead to many complications, especially in the immediate post-transplant period. In the past 10 years, there has been increasing interest in non-myeloablative, or reduced-intensity, conditioning transplants.⁶ These “mini transplants” involve smaller doses of chemotherapy or radiation, which do not totally eradicate the bone marrow; after the transplant a degree of chimerism develops where the donor and recipient stem cells coexist. The medications in the preparative regimen also should be considered because they can affect pulmonary complications after transplant. Certain chemotherapeutic agents such as carmustine, bleomycin, and many others can lead to acute and chronic presentations of pulmonary diseases such as hypersensitivity pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome, and abnormal pulmonary function testing.

After the HSCT, GVHD can develop in more than 50% of allogeneic recipients.³ The incidence of GVHD has been reported to be increasing over the past 12 years.It is divided into acute GVHD (which traditionally happens in the first 100 days after transplant) and chronic GVHD (after day 100). This calendar-day–based system has been augmented based on a 2006 National Institutes of Health working group report emphasizing the importance of organ-specific features of chronic GVHD in the clinical presentation of GVHD.⁷ Histologic changes in chronic organ GVHD tend to include more fibrotic features, whereas in acute GVHD more inflammatory changes are seen. The NIH working group report also stressed the importance of obtaining a biopsy specimen for histopathologic review and interdisciplinary collaboration to arrive at a consensus diagnosis, and noted the limitations of using histologic changes as the sole determinant of a “gold standard” diagnosis.⁷ GVHD can directly predispose patients to pulmonary GVHD and indirectly predispose them to infectious complications because the mainstay of therapy for GVHD is increased immunosuppression.

Pretransplant Evaluation

Case Patient 1

A 56-year-old man is diagnosed with acute myeloid leukemia (AML) after presenting with signs and symptoms consistent with pancytopenia. He has a past medical history of chronic sinus congestion, arthritis, depression, chronic pain, and carpal tunnel surgery. He is employed as an oilfield worker and has a 40-pack-year smoking history, but he recently cut back to half a pack per day. He is being evaluated for allogeneic transplant with his brother as the donor and the planned conditioning regimen is total body irradiation (TBI), thiotepa, cyclophosphamide, and antithymocyte globulin with T-cell depletion. Routine pretransplant pulmonary function testing (PFT) reveals a restrictive pattern and he is sent for pretransplant pulmonary evaluation.

Physical exam reveals a chronically ill appearing man. He is afebrile, the respiratory rate is 16 breaths/min, blood pressure is 145/88 mm Hg, heart rate is 92 beats/min, and oxygen saturation is 95%. He is in no distress. Auscultation of the chest reveals slightly diminished breath sounds bilaterally but is clear and without wheezes, rhonchi, or rales. Heart exam shows regular rate and rhythm without murmurs, rubs, or gallops. Extremities reveal no edema or rashes. Otherwise, the remainder of the exam is normal. The patient’s PFT results are shown in Table 2.

• What aspects of this patient’s history put him at risk for pulmonary complications after transplantation?

Risk Factors for Pulmonary Complications

Predicting who is at risk for pulmonary complications is difficult. Complications are generally divided into infectious and noninfectious categories. Regardless of category, allogeneic HSCT recipients are at increased risk compared with autologous recipients, but even in autologous transplants, more than 25% of patients will develop pulmonary complications in the first year.⁸ Prior to transplant, patients undergo full PFT. Early on, many studies attempted to show relationships between various factors and post-transplant pulmonary complications. Factors that were implicated were forced expiratory volume in 1 second (FEV₁), diffusing capacity of the lung for carbon monoxide (Dlco), total lung capacity (TLC), GVHD prophylaxis, TBI, and FEV₁/forced vital capacity (FEV₁/FVC) ratio.^9-15 Generally, poor baseline pulmonary functional status has been shown to correlate with higher risk for pulmonary complications. The most widely accepted pre-transplant PFT values examined for determining risk for developing pulmonary complications are FEV₁ and Dlco.

Another sometimes overlooked risk before transplantation is restrictive lung disease. One study showed a twofold increase in respiratory failure and mortality if there was pretransplant restriction based on TLC < 80%.¹⁶

An interesting study by one group in pretransplant evaluation found decreased muscle strength by maximal inspiratory muscle strength (PImax), maximal expiratory muscle strength (PEmax), dominant hand grip strength, and 6-minute walk test (6MWT) distance prior to allogeneic transplant, but did not find a relationship between these variables and mortality.¹⁷ While this study had a small sample size, these findings likely deserve continued investigation.¹⁸

• What methods are used to calculate risk for complications?

Risk Scoring Systems

Several pretransplantation risk scores have been developed. In a study that looked at more than 2500 allogeneic transplants, Parimon et al showed that risk of mortality and respiratory failure could be estimated prior to transplant using a scoring system—the Lung Function Score (LFS)—that combines the FEV₁ and Dlco.¹⁹ They assigned a score to the FEV₁ and Dlco based on the percentage of predicted values on PFT. Values greater than 80% were assigned 1 point, values 70% to 80% 2 points, 60% to 70% 3 points, and less than 60% 4 points. Combining the values for the FEV₁ and Dlco provides the LFS. A normal score is 2 (1 point each for FEV₁ and Dlco values > 80%) and is category I. A score of 3–4 is mildly decreased, category II; a score of 5–6 is moderately decreased, category III; and 7–8 is severely decreased, category IV. The hazard ratios (HR) for acute respiratory failure after transplant were 1.4, 2.2, and 3.1 for categories II, III, and IV, respectively. The HRs for mortality were 1.2, 2.2, and 2.7 for the same categories.¹⁹ This LFS has been used post-transplantation as well to categorize pulmonary GVHD.²⁰

The Pretransplantation Assessment of Mortality score, initially developed in 2006, predicts mortality within the first 2 years after HSCT based on 8 clinical factors: disease risk, age at transplant, donor type, conditioning regimen, and markers of organ function (percentage of predicted FEV₁, percentage of predicted Dlco, serum creatinine level, serum alanine aminotransferase level). Given the increased use of reduced-intensity conditioning regimens, the authors reevaluated the PAM score and following this analysis, creatinine, percent predicted Dlco, and liver function tests were found to no longer be statistically significant and were removed from the PAM score in 2015.^21,22 Another widely used score is the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI),²³ which predicts mortality following allogeneic stem cell transplantation. The HCT-CI also uses the FEV₁ and the Dlco as the 2 objective measures of pulmonary function.²³ While these pulmonary tests help with risk stratification, they are not perfect and it is not advised to use an isolated low Dlco to exclude individuals from transplant.²⁴ Recently, Coffey et al looked at the practice of correcting Dlco for hemoglobin by the Cotes method as suggested by the American Thoracic Society (ATS) versus the Dinakara method that was used in the HCT-CI.²⁵ In this study, the use of the Cotes method resulted in an elevated HCT-CI in 45% of patients, and in 33% it resulted in higher mortality risk predictions. Since the HCT-CI is validated using the Dinakara method, that method should be used in the HCT-CI calculations.²⁵

• What other preoperative testing or interventions should be considered in this patient?

Since there is a high risk of infectious complications after transplant, the question of whether pretransplantation patients should undergo screening imaging may arise. There is no evidence that routine chest computed tomography (CT) reduces the risk of infectious complications after transplantation.²⁶ An area that may be insufficiently addressed in the pretransplantation evaluation is smoking cessation counseling.²⁷ Studies have shown an elevated risk of mortality in smokers.^28-30 Others have found a higher incidence of respiratory failure but not an increased mortality.³¹ Overall, with the good rates of smoking cessation that can be accomplished, smokers should be counseled to quit before transplantation.

In summary, patients should undergo full PFTs prior to transplantation to help stratify risk for pulmonary complications and mortality and to establish a clinical baseline. The LFS (using FEV₁ and Dlco) can help categorize risk of respiratory failure and mortality after transplant. Absolute cut-off values for FEV₁ and Dlco are debated, but < 40% predicted and < 30% to 40% predicted, respectively, are considered contraindications to transplant. Smoking cessation should be advised if applicable during the pretransplant visit and optimization of reversible lung conditions should be stressed. There are no formal recommendations about reducing risk of early complications, but early mobilization, incentive spirometry, and use of inhalers if there is any history of obstructive lung disease should be considered.

Case Patient 1 Conclusion

The patient undergoes transplantation due to his lack of other treatment options. Evaluation prior to transplant, however, shows that he is at high risk for pulmonary complications. He has a LFS of 7 prior to transplant (using the Dlco corrected for hemoglobin), which puts him in class IV, with a HR of 3.1 for early respiratory failure and a HR of 2.7 for mortality. Additionally, he is still smoking at the time of transplantation. He does well immediately after transplantation, but has a complicated course with worsening mixed restrictive and obstructive pulmonary function abnormality. He becomes oxygen dependent and eventually undergoes video-assisted thoracoscopic surgery (VATS), which shows both usual interstitial pneumonia and restrictive bronchiolitis with changes consistent with mild to moderate pulmonary hypertension. He dies 2 years to the month after transplantation.

Early Infectious Pulmonary Complications

Case Patient 2

A 27-year-old man with a medical history significant for AML and allogeneic HSCT presents with cough productive of a small amount of clear to white sputum, dyspnea on exertion, and fevers for 1 week. He also has mild nausea and a decrease in appetite. He underwent HSCT 2.5 months prior to admission, which was a matched unrelated bone marrow transplant with TBI and cyclophosphamide conditioning. His past medical history is significant only for exercise-induced asthma for which he takes a rescue inhaler infrequently prior to transplantation. His pretransplant PFTs showed normal spirometry with an FEV₁ of 106% of predicted and Dlco of 54% of predicted. He does not smoke. His post-transplant medical course was complicated by severe acute skin GVHD as well as diarrhea, with sigmoidoscopy showing GVHD.

Physical exam is notable for fever of 101.0°F, heart rate 80 beats/min, respiratory rate 16 breaths/ min, and blood pressure 142/78 mm Hg; an admission oxygen saturation is 93% on room air. Lungs show bibasilar crackles and the remainder of the exam is normal. Laboratory testing shows a white blood cell count of 2400 cells/μL, hemoglobin 7.6 g/dL, and platelet count 66 × 10³/μL. Creatinine is 1.0 mg/dL. Chest radiograph shows ill-defined bilateral lower-lobe infiltrates. CT scans are shown in the Figure.

• For which infectious complications is this patient most at risk?

Pneumonia

A prospective trial in the HSCT population reported a pneumonia incidence rate of 68%, and pneumonia is more common in allogeneic HSCT with prolonged immunosuppressive therapy.³² Development of pneumonia within 100 days of transplant directly correlates with nonrelapsed mortality.³³ Early detection is key, and bronchoscopy within the first 5 days of symptoms has been shown to change therapy in approximately 40% of cases but has not been shown to affect mortality.³⁴ The clinical presentation of pneumonia in the HSCT population can be variable because of the presence of neutropenia and profound immunosuppression. Traditionally accepted diagnostic criteria of fevers, sputum production, and new infiltrates should be used with caution, and an appropriately high index of suspicion should be maintained. Progression to respiratory failure, regardless of causative organism of infection, portends a poor prognosis, with mortality rates estimated at 70% to 90%.^35,36 Several transplant-specific factors may affect early infections. For instance, UCB transplants have been found to have a higher incidence of invasive aspergillosis and cytomegalovirus (CMV) infections but without higher mortality attributed to the infections.³⁷

Bacterial Pneumonia

Bacterial pneumonia accounts for 20% to 50% of pneumonia cases in HSCT recipients.³⁸ Gram-negative organisms, specifically Pseudomonas aeruginosa and Escherichia coli, were reported to be the most common pathologic bacteria in recent prospective trials, whereas previous retrospective trials showed that common community-acquired organisms were the most common cause of pneumonia in HSCT recipients.^32,39 This underscores the importance of being aware of the clinical prevalence of microorganisms and local antibiograms, along with associated institutional susceptibility profiles. Initiation of immediate empiric broad-spectrum antibiotics is essential when bacterial pneumonia is suspected.

Viral Pneumonia

The prevalence of viral pneumonia in stem cell transplant recipients is estimated at 28%,³² with most cases being caused by community viral pathogens such as rhinovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza.³⁹ The prevention, prophylaxis, and early treatment of viral pneumonias, specifically CMV infection, have decreased the mortality associated with early pneumonia after HSCT. Co-infection with bacterial organisms must be considered and has been associated with increased mortality in the intensive care unit setting.⁴⁰

Supportive treatment with rhinovirus infection is sufficient as the disease is usually self-limited in immunocompromised patients. In contrast, infection with RSV in the lower respiratory tract is associated with increased mortality in prior reports, and recent studies suggest that further exploration of prophylaxis strategies is warranted.⁴¹ Treatment with ribavirin remains the backbone of therapy, but drug toxicity continues to limit its use. The addition of immunomodulators such as RSV immune globulin or palivizumab to ribavirin remains controversial, but a retrospective review suggests that early treatment may prevent progression to lower respiratory tract infection and lead to improved mortality.⁴² Infection with influenza A/B must be considered during influenza season. Treatment with oseltamivir may shorten the duration of disease when influenza A/B or parainfluenza are detected. Reactivation of latent herpes simplex virus during the pre-engraftment phase should also be considered. Treatment is similar to that in nonimmunocompromised hosts. When CMV pneumonia is suspected, careful history regarding compliance with prophylactic antivirals and CMV status of both the recipient and donor are key. A presumptive diagnosis can be made with the presence of appropriate clinical scenario, supportive radiographic images showing areas of ground-glass opacification or consolidation, and positive CMV polymerase chain reaction (PCR) assay. Visualization of inclusion bodies on lung biopsy tissue remains the gold standard for diagnosis. Treatment consists of CMV immunoglobulin and ganciclovir.

Fungal Pneumonia

Early fungal pneumonias have been associated with increased mortality in the HSCT population.⁴³ Clinical suspicion should remain high and compliance with antifungal prophylaxis should be questioned thoroughly. Invasive aspergillosis (IA) remains the most common fungal infection. A bimodal distribution of onset of infection peaking on day 16 and again on day 96 has been described in the literature.⁴⁴ Patients often present with classic pneumonia symptoms, but these may be accompanied by hemoptysis. Proven IA diagnosis requires visualization of fungal forms from biopsy or needle aspiration or a positive culture obtained in a sterile fashion.⁴⁵ Most clinical data comes from experience with probable and possible diagnosis of IA. Bronchoalveolar lavage with testing with Aspergillus galactomannan assay has been shown to be clinically useful in establishing the clinical diagnosis in the HSCT population.⁴⁶ Classic air-crescent findings on chest CT are helpful in establishing a possible diagnosis, but retrospective analysis reveals CT findings such as focal infiltrates and pulmonary nodular patterns are more common.⁴⁷ First-line treatment with voriconazole has been shown to decrease short-term mortality attributable to IA but has not had an effect on long-term, all-cause mortality.⁴⁸ Surgical resection is reserved for patients with refractory disease or patients presenting with massive hemoptysis.

Mucormycosis is an emerging disease with ever increasing prevalence in the HSCT population, reflecting the improved prophylaxis and treatment of IA. Initial clinical presentation is similar to IA, most commonly affecting the lung, although craniofacial involvement is classic for mucormycosis, especially in HSCT patients with diabetes.⁴⁹Mucor infections can present with massive hemoptysis due to tissue invasion and disregard for tissue and fascial planes. Diagnosis of mucormycosis is associated with as much as a six-fold increase in risk for death. Diagnosis requires identification of the organism by examination or culture and biopsy is often necessary.^50,51 Amphotericin B remains first-line therapy as mucormycosis is resistant to azole antifungals, with higher doses recommended for cerebral involvement.⁵²

Candida pulmonary infections during the early HSCT period are becoming increasingly rare due to widespread use of fluconazole prophylaxis and early treatment of mucosal involvement during neutropenia. Endemic fungal infections such as blastomycosis, coccidioidomycosis, and histoplasmosis should be considered in patients inhabiting specific geographic areas or with recent travel to these areas.

• What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis. ^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

• Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

• What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.

Diffuse Alveolar Hemorrhage

DAH is clinical syndrome consisting of diffuse alveolar infiltrates on pulmonary imaging combined with progressively bloodier return per aliquot during BAL in 3 different subsegments or more than 20% hemosiderin-laden macrophages on BAL fluid evaluation. Classically, DAH is defined in the absence of pulmonary infection or cardiac dysfunction. The pathophysiology is thought to be related to inflammation of pulmonary vasculature within the alveolar walls leading to alveolitis. Although no prospective trials exist, early use of high-dose corticosteroid therapy is thought to improve outcomes;^64,65 a recent study, however, showed low-dose steroids may be associated with the lowest mortality.⁶⁶ Mortality is directly linked to the presence of superimposed infection, need for mechanical ventilation, late onset, and development of multiorgan failure.⁶⁷

Idiopathic Pneumonia Syndrome

IPS is a complex clinical syndrome whose pathology is felt to stem from a variety of possible lung insults such as direct myeloablative drug toxicity, occult pulmonary infection, or cytokine-driven inflammation. The ATS published an article further subcategorizing IPS as different clinical entities based upon whether the primary insult involves the vascular endothelium, interstitial tissue, and airway tissue, truly idiopathic, or unclassified.⁶⁸ In clinical practice, IPS is defined as widespread alveolar injury in the absence of evidence of renal failure, heart failure, and excessive fluid resuscitation. In addition, negative testing for a variety of bacterial, viral, and fungal causes is also necessary.⁶⁹ Clinical syndromes included within the IPS definition are ARDS, acute interstitial pneumonia, DAH, cryptogenic organizing pneumonia, and BOS.⁷⁰ Risk factors for developing IPS include TBI, older age of recipient, acute GVHD, and underlying diagnosis of AML or myelodysplastic syndrome.¹² In addition, it has been shown that risk for developing IPS is lower in patients undergoing allogeneic HSCT who receive non-myeloablative conditioning regimens.⁷¹ The pathologic finding in IPS is diffuse alveolar damage. A 2006 study in which investigators reviewed BAL samples from patients with IPS found that 3% of the patients had PCR evidence of human metapneumovirus infection, and a study in 2015 found PCR evidence of infection in 53% of BAL samples from patients diagnosed with IPS.^72,73 This fuels the debate on whether IPS is truly an infection-driven process where the source of infection, pulmonary or otherwise, simply escapes detection. Various surfactant proteins, which play a role in decreasing surface tension within the alveolar interface and function as mediators within the innate immunity of the lung, have been studied in regard to development of IPS. Small retrospective studies have shown a trend toward lower pre-transplant serum protein surfactant D and the development of IPS.⁷⁴

The diagnosis of IPS does not require pathologic diagnosis in most circumstances. The correct clinical findings in association with a negative infectious workup lead to a presumptive diagnosis of IPS. The extent of the infectious workup that must be completed to adequately rule out infection is often a difficult clinical question. Recent recommendations include BAL fluid evaluation for routine bacterial cultures, appropriate viral culture, and consideration of PCR testing to evaluate for Mycoplasma, Chlamydia, and Aspergillus antigens.⁷⁵ Transbronchial biopsy continues to appear in recommendations, but is not routinely performed and should be completed as the patient’s clinical status permits.^8,68 Table 3 reviews basic features of early noninfectious pulmonary complications.

• What treatment should be offered to the patient with diffuse alveolar damage on biopsy?

Treatment consists of supportive care and empiric broad-spectrum antibiotics with consideration of high-dose corticosteroids. Based upon early studies in murine models implicating TNF, pilot studies were performed evaluating etanercept as a possible safe and effective addition to high-dose systemic corticosteroids.⁷⁷ Although these results were promising, data from a truncated randomized control clinical trial failed to show improvement in patient response in the adult population.⁷⁶ More recent data from the same author suggests that pediatric populations with IPS are, however, responsive to etanercept and high-dose corticosteroid therapy.⁷⁸ When IPS develops as a late complication, treatment with high-dose corticosteroids (2 mg/kg/day) and etanercept (0.4 mg/kg twice weekly) has been shown to improve 2-year survival.⁷⁹

Case Patient 2 Conclusion

The patient is started on steroids and makes a speedy recovery. He is successfully extubated 5 days later.

Conclusion

Careful pretransplant evaluation, including a full set of pulmonary function tests, can help predict a patient’s risk for pulmonary complications after transplant, allowing risk factor modification strategies to be implemented prior to transplant, including smoking cessation. It also helps identify patients at high risk for complications who will require closer monitoring after transplantation. Early posttransplant complications include infectious and noninfectious entities. Bacterial, viral, and fungal pneumonias are in the differential of infectious pneumonia, and bronchoscopy can be helpful in establishing a diagnosis. A common, important noninfectious cause of early pulmonary complications is IPS, which is treated with steroids and sometimes anti-TNF therapy.

“This is terrific news,” said US Department of Veterans Affairs (VA) Secretary Robert Wilkie, noting that the VA is the largest single provider of hepatitis C virus (HCV) care in the US. “Diagnosing, treating, and curing hepatitis C virus infection among veterans has been a significant priority for VA.” According to the Review of Hepatitis C Virus Care within the Veterans Health Administration, published last month by the VA Office of Inspector General (OIG), the VA cares for more than 180,000 confirmed patients who are disproportionately affected by HCV infection, at rates about 3 times that of the national average.

As of March, nearly 116,000 veterans had started all-oral HCV medications. Almost 100,000 have completed treatment and are now cured. As an article in Forbes magazine pointed out, that is a story very different from the one reported just a few years earlier, when HCV treatment was out of reach for the tens of thousands of service members seriously ill with HCV, most of whom contracted it during blood transfusions in the Vietnam War.

The good news is due largely to the use of highly effective direct-acting antivirals (DAAs), which have revolutionized HCV treatment. Before 2014, HCV treatment required weekly interferon injections for up to a year, with low cure rates (35%-55%) and significant physical and psychiatric adverse effects (AEs), leading to frequent early discontinuation. Of the approximately 180,000 veterans in VA care at that time who had been diagnosed with chronic HCV infection, only 12,000 had been treated and cured. More than 30,000 had advanced liver disease.

In 2014, the VA launched an “aggressive program” to identify all undiagnosed veterans with HCV, link them to care, and offer them treatment with the new medications: sofosbuvir (Sovaldi) and simeprevir (Olysio). They have few AEs and can be administered once daily for as few as 8 weeks.

However, those drugs were incredibly expensive, prohibitively so for many people. Sovaldi cost $1,000 a pill. But the VA, allowed by law to negotiate prices, brought down the price. The VA estimated that the drugs would cost roughly $750 million and provide about 60,000 treatments over 2017 and 2018, at about $25,300 per service member .

The VA then began treating close to 2,000 veterans with HCV every week—nearly 1 treatment started every minute of every workday. As a result, by the next year the overall death rate had dropped dramatically. Veterans cured of HCV were also 84% less likely to develop liver cancer.

The decision to disqualify a patient from receiving HCV treatment must be made on a case-by-case basis by individual providers in consultation with their patients, the OIG says. If a patient is deferred for treatment based on “problematic levels of alcohol or substance use,” the report adds, he/she should be referred for substance use treatment and must have a plan for re-evaluation for HCV treatment within 3 to 6 months. However, the VHA notes that patients with drug or alcohol addiction “should not be automatically excluded from hepatitis C treatment.”

The VA says it is on track to treat more than 125,000 veterans with HCV by October. As of March, fewer than 27,000 remained to be treated.

“This is terrific news,” said US Department of Veterans Affairs (VA) Secretary Robert Wilkie, noting that the VA is the largest single provider of hepatitis C virus (HCV) care in the US. “Diagnosing, treating, and curing hepatitis C virus infection among veterans has been a significant priority for VA.” According to the Review of Hepatitis C Virus Care within the Veterans Health Administration, published last month by the VA Office of Inspector General (OIG), the VA cares for more than 180,000 confirmed patients who are disproportionately affected by HCV infection, at rates about 3 times that of the national average.

As of March, nearly 116,000 veterans had started all-oral HCV medications. Almost 100,000 have completed treatment and are now cured. As an article in Forbes magazine pointed out, that is a story very different from the one reported just a few years earlier, when HCV treatment was out of reach for the tens of thousands of service members seriously ill with HCV, most of whom contracted it during blood transfusions in the Vietnam War.

The good news is due largely to the use of highly effective direct-acting antivirals (DAAs), which have revolutionized HCV treatment. Before 2014, HCV treatment required weekly interferon injections for up to a year, with low cure rates (35%-55%) and significant physical and psychiatric adverse effects (AEs), leading to frequent early discontinuation. Of the approximately 180,000 veterans in VA care at that time who had been diagnosed with chronic HCV infection, only 12,000 had been treated and cured. More than 30,000 had advanced liver disease.

In 2014, the VA launched an “aggressive program” to identify all undiagnosed veterans with HCV, link them to care, and offer them treatment with the new medications: sofosbuvir (Sovaldi) and simeprevir (Olysio). They have few AEs and can be administered once daily for as few as 8 weeks.

However, those drugs were incredibly expensive, prohibitively so for many people. Sovaldi cost $1,000 a pill. But the VA, allowed by law to negotiate prices, brought down the price. The VA estimated that the drugs would cost roughly $750 million and provide about 60,000 treatments over 2017 and 2018, at about $25,300 per service member .

The VA then began treating close to 2,000 veterans with HCV every week—nearly 1 treatment started every minute of every workday. As a result, by the next year the overall death rate had dropped dramatically. Veterans cured of HCV were also 84% less likely to develop liver cancer.

The decision to disqualify a patient from receiving HCV treatment must be made on a case-by-case basis by individual providers in consultation with their patients, the OIG says. If a patient is deferred for treatment based on “problematic levels of alcohol or substance use,” the report adds, he/she should be referred for substance use treatment and must have a plan for re-evaluation for HCV treatment within 3 to 6 months. However, the VHA notes that patients with drug or alcohol addiction “should not be automatically excluded from hepatitis C treatment.”

The VA says it is on track to treat more than 125,000 veterans with HCV by October. As of March, fewer than 27,000 remained to be treated.

“This is terrific news,” said US Department of Veterans Affairs (VA) Secretary Robert Wilkie, noting that the VA is the largest single provider of hepatitis C virus (HCV) care in the US. “Diagnosing, treating, and curing hepatitis C virus infection among veterans has been a significant priority for VA.” According to the Review of Hepatitis C Virus Care within the Veterans Health Administration, published last month by the VA Office of Inspector General (OIG), the VA cares for more than 180,000 confirmed patients who are disproportionately affected by HCV infection, at rates about 3 times that of the national average.

As of March, nearly 116,000 veterans had started all-oral HCV medications. Almost 100,000 have completed treatment and are now cured. As an article in Forbes magazine pointed out, that is a story very different from the one reported just a few years earlier, when HCV treatment was out of reach for the tens of thousands of service members seriously ill with HCV, most of whom contracted it during blood transfusions in the Vietnam War.

The good news is due largely to the use of highly effective direct-acting antivirals (DAAs), which have revolutionized HCV treatment. Before 2014, HCV treatment required weekly interferon injections for up to a year, with low cure rates (35%-55%) and significant physical and psychiatric adverse effects (AEs), leading to frequent early discontinuation. Of the approximately 180,000 veterans in VA care at that time who had been diagnosed with chronic HCV infection, only 12,000 had been treated and cured. More than 30,000 had advanced liver disease.

In 2014, the VA launched an “aggressive program” to identify all undiagnosed veterans with HCV, link them to care, and offer them treatment with the new medications: sofosbuvir (Sovaldi) and simeprevir (Olysio). They have few AEs and can be administered once daily for as few as 8 weeks.

However, those drugs were incredibly expensive, prohibitively so for many people. Sovaldi cost $1,000 a pill. But the VA, allowed by law to negotiate prices, brought down the price. The VA estimated that the drugs would cost roughly $750 million and provide about 60,000 treatments over 2017 and 2018, at about $25,300 per service member .

The VA then began treating close to 2,000 veterans with HCV every week—nearly 1 treatment started every minute of every workday. As a result, by the next year the overall death rate had dropped dramatically. Veterans cured of HCV were also 84% less likely to develop liver cancer.

The decision to disqualify a patient from receiving HCV treatment must be made on a case-by-case basis by individual providers in consultation with their patients, the OIG says. If a patient is deferred for treatment based on “problematic levels of alcohol or substance use,” the report adds, he/she should be referred for substance use treatment and must have a plan for re-evaluation for HCV treatment within 3 to 6 months. However, the VHA notes that patients with drug or alcohol addiction “should not be automatically excluded from hepatitis C treatment.”

The VA says it is on track to treat more than 125,000 veterans with HCV by October. As of March, fewer than 27,000 remained to be treated.

Adolescents with severe obesity and cognitive impairment or developmental delay (CI/DD) lost as much weight, and at a similar rate, as their typically developing peers following laparoscopic sleeve gastrectomy (LSG), according in an observational study.

“On the basis of these new data, LSG appears to be a viable and successful short-term weight-management tool for adolescents with CI/DD, who are established as particularly vulnerable to obesity and secondary health concerns,” wrote Sarah E. Hornack, PhD, a psychologist with Children’s National Health System and George Washington University, both in Washington, and her associates.

“In fact, there may be advantages to undergoing surgery during adolescence rather than waiting until adulthood for this population,” they wrote in the journal Pediatrics. With more supports likely in place for teens undergoing this surgery, they won’t be “going it alone,” the authors noted, which “could translate to better cooperation with parental guidance regarding surgery requirements, including diet and exercise recommendations.”

Despite higher rates of obesity and related medical issues among youth with CI/DD, little research explores effective interventions in this population, the authors wrote.

They therefore compared outcomes among a group of 63 teens with obesity who underwent bariatric surgery during 2010-2017. The adolescents, who had a body mass index (BMI) of at least 40 kg/m² or one of at least 35 kg/m² with a medical comorbidity, first underwent preoperative psychological evaluations involving a cognitive assessment. The 17 adolescents with an IQ less than 80 were classified as having CI/DD, leaving 46 without CI/DD. Three teens had Down syndrome.

Age, sex, and BMI before surgery were similar in those with CI/DD versus those without. The majority of participants overall were female (65%) and black (57%) with an average age of 17 years and an average BMI of 51.2. Whites comprised 24% of participants while 17% were Hispanic and 1% another race/ethnicity.

The findings revealed that IQ did not predict weight loss. The percentage of excess BMI lost (%EBMIL) and rate of excess weight loss remained similar between those with and without CI/DD, though “a trend for a higher rate of change in %EBMIL for those individuals with CI/DD” suggested “they may experience greater rates of weight loss over time than their typically developing peers,” the authors reported. However, the proportion of participants assessed decreased with each follow-up, from 59 at 3 months to 14 at 24 months.

In addition to the small population, short-term follow-up and loss to follow-up, another study limitation is the lack of a control group of CI/DD patients who did not undergo bariatric surgery and instead received a behavioral intervention or other therapy.

But the authors noted existing evidence that “younger children respond better to behavioral interventions than adolescents do, suggesting that older youth may require a different treatment approach.” In addition, “bariatric surgery performed earlier in the trajectory of large weight gain has also been shown to lead to greater resolution of obesity, suggesting that waiting for adulthood can be detrimental,” they wrote.
 

SOURCE: Hornack SE et al. Pediatrics. 2019 Apr 15. doi: 10.1542/peds.2018-2908.

Adolescents with severe obesity and cognitive impairment or developmental delay (CI/DD) lost as much weight, and at a similar rate, as their typically developing peers following laparoscopic sleeve gastrectomy (LSG), according in an observational study.

“On the basis of these new data, LSG appears to be a viable and successful short-term weight-management tool for adolescents with CI/DD, who are established as particularly vulnerable to obesity and secondary health concerns,” wrote Sarah E. Hornack, PhD, a psychologist with Children’s National Health System and George Washington University, both in Washington, and her associates.

“In fact, there may be advantages to undergoing surgery during adolescence rather than waiting until adulthood for this population,” they wrote in the journal Pediatrics. With more supports likely in place for teens undergoing this surgery, they won’t be “going it alone,” the authors noted, which “could translate to better cooperation with parental guidance regarding surgery requirements, including diet and exercise recommendations.”

Despite higher rates of obesity and related medical issues among youth with CI/DD, little research explores effective interventions in this population, the authors wrote.

They therefore compared outcomes among a group of 63 teens with obesity who underwent bariatric surgery during 2010-2017. The adolescents, who had a body mass index (BMI) of at least 40 kg/m² or one of at least 35 kg/m² with a medical comorbidity, first underwent preoperative psychological evaluations involving a cognitive assessment. The 17 adolescents with an IQ less than 80 were classified as having CI/DD, leaving 46 without CI/DD. Three teens had Down syndrome.

Age, sex, and BMI before surgery were similar in those with CI/DD versus those without. The majority of participants overall were female (65%) and black (57%) with an average age of 17 years and an average BMI of 51.2. Whites comprised 24% of participants while 17% were Hispanic and 1% another race/ethnicity.

The findings revealed that IQ did not predict weight loss. The percentage of excess BMI lost (%EBMIL) and rate of excess weight loss remained similar between those with and without CI/DD, though “a trend for a higher rate of change in %EBMIL for those individuals with CI/DD” suggested “they may experience greater rates of weight loss over time than their typically developing peers,” the authors reported. However, the proportion of participants assessed decreased with each follow-up, from 59 at 3 months to 14 at 24 months.

In addition to the small population, short-term follow-up and loss to follow-up, another study limitation is the lack of a control group of CI/DD patients who did not undergo bariatric surgery and instead received a behavioral intervention or other therapy.

But the authors noted existing evidence that “younger children respond better to behavioral interventions than adolescents do, suggesting that older youth may require a different treatment approach.” In addition, “bariatric surgery performed earlier in the trajectory of large weight gain has also been shown to lead to greater resolution of obesity, suggesting that waiting for adulthood can be detrimental,” they wrote.
 

SOURCE: Hornack SE et al. Pediatrics. 2019 Apr 15. doi: 10.1542/peds.2018-2908.

Adolescents with severe obesity and cognitive impairment or developmental delay (CI/DD) lost as much weight, and at a similar rate, as their typically developing peers following laparoscopic sleeve gastrectomy (LSG), according in an observational study.

“On the basis of these new data, LSG appears to be a viable and successful short-term weight-management tool for adolescents with CI/DD, who are established as particularly vulnerable to obesity and secondary health concerns,” wrote Sarah E. Hornack, PhD, a psychologist with Children’s National Health System and George Washington University, both in Washington, and her associates.

“In fact, there may be advantages to undergoing surgery during adolescence rather than waiting until adulthood for this population,” they wrote in the journal Pediatrics. With more supports likely in place for teens undergoing this surgery, they won’t be “going it alone,” the authors noted, which “could translate to better cooperation with parental guidance regarding surgery requirements, including diet and exercise recommendations.”

Despite higher rates of obesity and related medical issues among youth with CI/DD, little research explores effective interventions in this population, the authors wrote.

They therefore compared outcomes among a group of 63 teens with obesity who underwent bariatric surgery during 2010-2017. The adolescents, who had a body mass index (BMI) of at least 40 kg/m² or one of at least 35 kg/m² with a medical comorbidity, first underwent preoperative psychological evaluations involving a cognitive assessment. The 17 adolescents with an IQ less than 80 were classified as having CI/DD, leaving 46 without CI/DD. Three teens had Down syndrome.

Age, sex, and BMI before surgery were similar in those with CI/DD versus those without. The majority of participants overall were female (65%) and black (57%) with an average age of 17 years and an average BMI of 51.2. Whites comprised 24% of participants while 17% were Hispanic and 1% another race/ethnicity.

The findings revealed that IQ did not predict weight loss. The percentage of excess BMI lost (%EBMIL) and rate of excess weight loss remained similar between those with and without CI/DD, though “a trend for a higher rate of change in %EBMIL for those individuals with CI/DD” suggested “they may experience greater rates of weight loss over time than their typically developing peers,” the authors reported. However, the proportion of participants assessed decreased with each follow-up, from 59 at 3 months to 14 at 24 months.

In addition to the small population, short-term follow-up and loss to follow-up, another study limitation is the lack of a control group of CI/DD patients who did not undergo bariatric surgery and instead received a behavioral intervention or other therapy.

But the authors noted existing evidence that “younger children respond better to behavioral interventions than adolescents do, suggesting that older youth may require a different treatment approach.” In addition, “bariatric surgery performed earlier in the trajectory of large weight gain has also been shown to lead to greater resolution of obesity, suggesting that waiting for adulthood can be detrimental,” they wrote.
 

SOURCE: Hornack SE et al. Pediatrics. 2019 Apr 15. doi: 10.1542/peds.2018-2908.

Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.

“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.

TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.

At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).

The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”

“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”

The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.

SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.

Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.

“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.

TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.

At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).

The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”

“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”

The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.

SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.

Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.

“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.

TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.

At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).

The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”

“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”

The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.

SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.

A 64-year-old man with type 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care A1C is 9.5%, and he is currently taking only metformin (1000 mg bid). You are considering the addition of an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and CV mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people (1 of every 11) now struggle to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of available medications that aim to lower blood glucose and improve diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The American Diabetes Association’s Standards of Medical Care in Diabetes points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin and the GLP-1 agonist liraglutide as agents that should be added to metformin and lifestyle modification for patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists/American College of Endocrinology guidelines include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in the strength of recommendation for each class is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s equal better mortality outcomes

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications (eg, metformin) prior to enrollment and during the trials. About half the patients analyzed were enrolled in trials that specifically evaluated those at elevated CV risk—notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group: hazard ratio [HR], 0.80; absolute risk difference [RD], –1%; number needed to treat [NNT], 100; GLP-1 agonist group: HR, 0.88; absolute RD, –0.6%; NNT, 167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR, 1.02; absolute RD, 0.1%). Both the SGLT-2 inhibitor (HR, 0.78; absolute RD, –0.9%; NNT, 111) and GLP-1 agonist (HR, 0.86; absolute RD, –0.5%; NNT, 200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR, 0.79; absolute RD, –0.8%; NNT, 125) and GLP-1 agonist (HR, 0.85; absolute RD, –0.5%; NNT, 200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR, 0.62; absolute RD, –1.1%; NNT, 91) and MI (HR, 0.86; absolute RD, –0.6%; NNT, 167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR, 0.67; absolute RD, –0.9; NNT, 111) or DPP-4 inhibitors (HR, 0.55; absolute RD, –1.1%; NNT, 91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups had lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists: HR, 2; absolute RD, 4.7%; number needed to harm [NNH], 21; SGLT-2 inhibitors: HR, 1.8; absolute RD, 5.8%; NNH, 17; and DPP-4 inhibitors: HR, 1.93; absolute RD, 3.1%; NNH, 32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR], 4.19; absolute RD, 6%; NNH, 16), but not of urinary tract infection or lower limb amputation—although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR, 1.58; absolute RD, 0.1%; NNH, 1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 medication classes.

However, there was relatively low heterogeneity among the studies included, which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown, because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[2]:99-101).

A 64-year-old man with type 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care A1C is 9.5%, and he is currently taking only metformin (1000 mg bid). You are considering the addition of an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and CV mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people (1 of every 11) now struggle to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of available medications that aim to lower blood glucose and improve diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The American Diabetes Association’s Standards of Medical Care in Diabetes points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin and the GLP-1 agonist liraglutide as agents that should be added to metformin and lifestyle modification for patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists/American College of Endocrinology guidelines include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in the strength of recommendation for each class is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s equal better mortality outcomes

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications (eg, metformin) prior to enrollment and during the trials. About half the patients analyzed were enrolled in trials that specifically evaluated those at elevated CV risk—notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group: hazard ratio [HR], 0.80; absolute risk difference [RD], –1%; number needed to treat [NNT], 100; GLP-1 agonist group: HR, 0.88; absolute RD, –0.6%; NNT, 167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR, 1.02; absolute RD, 0.1%). Both the SGLT-2 inhibitor (HR, 0.78; absolute RD, –0.9%; NNT, 111) and GLP-1 agonist (HR, 0.86; absolute RD, –0.5%; NNT, 200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR, 0.79; absolute RD, –0.8%; NNT, 125) and GLP-1 agonist (HR, 0.85; absolute RD, –0.5%; NNT, 200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR, 0.62; absolute RD, –1.1%; NNT, 91) and MI (HR, 0.86; absolute RD, –0.6%; NNT, 167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR, 0.67; absolute RD, –0.9; NNT, 111) or DPP-4 inhibitors (HR, 0.55; absolute RD, –1.1%; NNT, 91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups had lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists: HR, 2; absolute RD, 4.7%; number needed to harm [NNH], 21; SGLT-2 inhibitors: HR, 1.8; absolute RD, 5.8%; NNH, 17; and DPP-4 inhibitors: HR, 1.93; absolute RD, 3.1%; NNH, 32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR], 4.19; absolute RD, 6%; NNH, 16), but not of urinary tract infection or lower limb amputation—although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR, 1.58; absolute RD, 0.1%; NNH, 1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 medication classes.

However, there was relatively low heterogeneity among the studies included, which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown, because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[2]:99-101).

A 64-year-old man with type 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care A1C is 9.5%, and he is currently taking only metformin (1000 mg bid). You are considering the addition of an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and CV mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people (1 of every 11) now struggle to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of available medications that aim to lower blood glucose and improve diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The American Diabetes Association’s Standards of Medical Care in Diabetes points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin and the GLP-1 agonist liraglutide as agents that should be added to metformin and lifestyle modification for patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists/American College of Endocrinology guidelines include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in the strength of recommendation for each class is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s equal better mortality outcomes

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications (eg, metformin) prior to enrollment and during the trials. About half the patients analyzed were enrolled in trials that specifically evaluated those at elevated CV risk—notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group: hazard ratio [HR], 0.80; absolute risk difference [RD], –1%; number needed to treat [NNT], 100; GLP-1 agonist group: HR, 0.88; absolute RD, –0.6%; NNT, 167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR, 1.02; absolute RD, 0.1%). Both the SGLT-2 inhibitor (HR, 0.78; absolute RD, –0.9%; NNT, 111) and GLP-1 agonist (HR, 0.86; absolute RD, –0.5%; NNT, 200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR, 0.79; absolute RD, –0.8%; NNT, 125) and GLP-1 agonist (HR, 0.85; absolute RD, –0.5%; NNT, 200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR, 0.62; absolute RD, –1.1%; NNT, 91) and MI (HR, 0.86; absolute RD, –0.6%; NNT, 167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR, 0.67; absolute RD, –0.9; NNT, 111) or DPP-4 inhibitors (HR, 0.55; absolute RD, –1.1%; NNT, 91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups had lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists: HR, 2; absolute RD, 4.7%; number needed to harm [NNH], 21; SGLT-2 inhibitors: HR, 1.8; absolute RD, 5.8%; NNH, 17; and DPP-4 inhibitors: HR, 1.93; absolute RD, 3.1%; NNH, 32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR], 4.19; absolute RD, 6%; NNH, 16), but not of urinary tract infection or lower limb amputation—although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR, 1.58; absolute RD, 0.1%; NNH, 1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 medication classes.

However, there was relatively low heterogeneity among the studies included, which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown, because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[2]:99-101).

Patients with type 2 diabetes and chronic kidney disease (CKD) show significantly lower incidence of kidney failure and cardiovascular events after treatment with the sodium-glucose cotransporter 2 inhibitor canagliflozin, in the CREDENCE trial.

CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) is a double-blind, placebo-controlled trial involving 4,401 patients with type 2 diabetes and albuminuric CKD, who were randomized to either 100 mg of canagliflozin daily or placebo.

After a median follow-up of 2.62 years, there was a significant 30% lower risk of the primary outcome, which was a composite of end-stage kidney disease, a doubling of serum creatinine, or death from renal or cardiovascular causes, a highly significant difference at P = .00001.

Separately, there was a 32% lower risk of end-stage kidney disease, a 20% lower risk of cardiovascular death, MI, or stroke, and a 39% lower risk of hospitalization for heart failure, both significant differences. Patients treated with canagliflozin also had a 40% lower risk of a doubling of serum creatinine, and a 28% lower risk of dialysis, kidney transplantation, or renal death.

“These findings were observed despite very modest between-group differences in blood glucose level, weight, and blood pressure, and in contrast to previous concern about the initial acute reduction in the estimated GFR [glomerular filtration rate] observed with SGLT2 inhibitors,” wrote Vlado Perkovic, MD, from the George Institute for Global Health, University of New South Wales Sydney, and his coauthors. “This suggests that the mechanism of benefit is likely to be independent of glucose levels and may possibly stem from a reduction in intraglomerular pressure, with other possible mechanisms presently being studied.”

The trial was stopped early after reaching the prespecified efficacy criteria for early cessation. The authors estimated that 21.2 patients would need to be treated with canagliflozin to prevent one primary outcome.

There were no significant differences between the two groups in the rate of adverse and serious adverse events, including the risk of lower limb amputation and fracture.

The study was supported by Janssen Research and Development. Eighteen authors declared steering committee, support and consultancies with Janssen, and thirteen also declared personal fees from other pharmaceutical and private industry. Five authors were employees of Janssen.

SOURCE: Perkovic V et al. N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744.
 

Patients with type 2 diabetes and chronic kidney disease (CKD) show significantly lower incidence of kidney failure and cardiovascular events after treatment with the sodium-glucose cotransporter 2 inhibitor canagliflozin, in the CREDENCE trial.

CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) is a double-blind, placebo-controlled trial involving 4,401 patients with type 2 diabetes and albuminuric CKD, who were randomized to either 100 mg of canagliflozin daily or placebo.

After a median follow-up of 2.62 years, there was a significant 30% lower risk of the primary outcome, which was a composite of end-stage kidney disease, a doubling of serum creatinine, or death from renal or cardiovascular causes, a highly significant difference at P = .00001.

Separately, there was a 32% lower risk of end-stage kidney disease, a 20% lower risk of cardiovascular death, MI, or stroke, and a 39% lower risk of hospitalization for heart failure, both significant differences. Patients treated with canagliflozin also had a 40% lower risk of a doubling of serum creatinine, and a 28% lower risk of dialysis, kidney transplantation, or renal death.

“These findings were observed despite very modest between-group differences in blood glucose level, weight, and blood pressure, and in contrast to previous concern about the initial acute reduction in the estimated GFR [glomerular filtration rate] observed with SGLT2 inhibitors,” wrote Vlado Perkovic, MD, from the George Institute for Global Health, University of New South Wales Sydney, and his coauthors. “This suggests that the mechanism of benefit is likely to be independent of glucose levels and may possibly stem from a reduction in intraglomerular pressure, with other possible mechanisms presently being studied.”

The trial was stopped early after reaching the prespecified efficacy criteria for early cessation. The authors estimated that 21.2 patients would need to be treated with canagliflozin to prevent one primary outcome.

There were no significant differences between the two groups in the rate of adverse and serious adverse events, including the risk of lower limb amputation and fracture.

The study was supported by Janssen Research and Development. Eighteen authors declared steering committee, support and consultancies with Janssen, and thirteen also declared personal fees from other pharmaceutical and private industry. Five authors were employees of Janssen.

SOURCE: Perkovic V et al. N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744.
 

Patients with type 2 diabetes and chronic kidney disease (CKD) show significantly lower incidence of kidney failure and cardiovascular events after treatment with the sodium-glucose cotransporter 2 inhibitor canagliflozin, in the CREDENCE trial.

CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) is a double-blind, placebo-controlled trial involving 4,401 patients with type 2 diabetes and albuminuric CKD, who were randomized to either 100 mg of canagliflozin daily or placebo.

After a median follow-up of 2.62 years, there was a significant 30% lower risk of the primary outcome, which was a composite of end-stage kidney disease, a doubling of serum creatinine, or death from renal or cardiovascular causes, a highly significant difference at P = .00001.

Separately, there was a 32% lower risk of end-stage kidney disease, a 20% lower risk of cardiovascular death, MI, or stroke, and a 39% lower risk of hospitalization for heart failure, both significant differences. Patients treated with canagliflozin also had a 40% lower risk of a doubling of serum creatinine, and a 28% lower risk of dialysis, kidney transplantation, or renal death.

“These findings were observed despite very modest between-group differences in blood glucose level, weight, and blood pressure, and in contrast to previous concern about the initial acute reduction in the estimated GFR [glomerular filtration rate] observed with SGLT2 inhibitors,” wrote Vlado Perkovic, MD, from the George Institute for Global Health, University of New South Wales Sydney, and his coauthors. “This suggests that the mechanism of benefit is likely to be independent of glucose levels and may possibly stem from a reduction in intraglomerular pressure, with other possible mechanisms presently being studied.”

The trial was stopped early after reaching the prespecified efficacy criteria for early cessation. The authors estimated that 21.2 patients would need to be treated with canagliflozin to prevent one primary outcome.

There were no significant differences between the two groups in the rate of adverse and serious adverse events, including the risk of lower limb amputation and fracture.

The study was supported by Janssen Research and Development. Eighteen authors declared steering committee, support and consultancies with Janssen, and thirteen also declared personal fees from other pharmaceutical and private industry. Five authors were employees of Janssen.

SOURCE: Perkovic V et al. N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744.
 

Editor’s note: This is the second in a series of articles by Dr. Miller about challenges in outpatient psychiatry.

Mr. A lived a life that seemed glamorous to me. There were lunches with professional athletes, swank social events, and designer everything from clothes to cars. It was a world that I was not familiar with, and while I knew my patient worried about money, it seemed he had it. When he started therapy with me, Mr. A came to every session with a check. At some point, I realized that I had missed a switch in his mood. Despite his therapeutic level of lithium, Mr. A had become manic, and the expression of this mania took the form of even more spending. What started as an exciting lifestyle suddenly became tens of thousands of dollars of debt. I felt guilty that I initially did not see this as pathology, and as a young psychiatrist, I sought consultation with an older and wiser mentor.

After discussing the case, the consulting psychiatrist said to me, “Make sure you get paid; these cases are difficult.” In fact, in the midst of the chaos, Mr. A had stopped bringing a check to the sessions. I sent monthly statements, and they went unpaid. He didn’t have the money for his living expenses and I let this go on without addressing it for much too long. Soon, Mr. A’s debt to me was just one more stress in his life and while I knew I would not pursue reimbursement through legal channels, I did encourage him to find a psychiatrist who was in his insurance network, something he did not want to do. I was too embarrassed to tell the consulting psychiatrist that Mr. A had already accrued well over a thousand dollars in unpaid professional fees. In my mind, I was offering pro bono care because the patient’s financial circumstances had changed, and because I felt guilty that I had not recognized this as mania sooner.

In a 2011 Shrink Rap blog post, Jesse Hellman, MD, a psychiatrist in private practice in Towson, Md., wrote about the meaning of payment in psychotherapy:

“Money is something loaded with meaning to most people. What does it mean that the patient forgets to pay? Does it mean ‘if you really cared about me you would not charge me’? Is it a reflection of anger for something that occurred in the last session? Is it a displacement of feelings from something else (‘my boss didn’t give me the raise I expected’)? Is it completely inadvertent (Freud famously said ‘Sometimes a cigar is only a cigar’)?”

There are so many possibilities, and the psychodynamic therapist wants to understand them. How the patient relates to the therapist is some part of how he relates to others. The patient hopefully starts to watch his own actions and attitudes and also tries to understand them. A nonjudgmental stance helps the patient do this.

The therapist himself needs to be comfortable dealing with the subject of money. Sometimes beginning physicians fluctuate between feeling they are too inexperienced to be paid and feeling that they deserve anything they ask. We physicians might even (unfortunately) take on the attitudes of the insurance companies themselves (“Identification with the Aggressor”).

The blog post was flooded with comments –120 in total, and more comments than any other single Shrink Rap post received for the blog’s 12-year run.

Steven Reidbord, MD, is a psychiatrist in private practice in San Francisco and also a blogger. Dr. Reidbord conversed with me through email about patients who don’t pay.

“In years past, I’ve had a few patients who met with me a few times, always ‘forgetting’ their payment and offering it ‘next time,’ until after three or four sessions, I refused to see them. I always wondered what such patients were thinking, as obviously this arrangement wouldn’t last long. Did they tell themselves they’d pay me at some point, in effect fooling themselves? Was it conscious theft of my services? A couple years ago, I started accepting charge cards, and perhaps as a result, this hasn’t happened. While it’s always useful to consider individual dynamics in explaining such behavior, it’s also important to consider normative psychology: Make it easier to pay, and more people will.”

While payment for out-of-network services is often clear cut – the patients pay and then requests reimbursement from their insurer – the logistics often are confusing for the patient. He or she may believe that she has excellent coverage, only to learn that the out-of-network deductible is very high, or that reimbursement is based on “usual and customary fees” that are much lower than his psychiatrist’s fees. Sometimes people take on the cost of psychiatric care and discover that it costs more than they assumed, or they have a change in their financial circumstances, as my patient did. Sometimes a parent is paying for treatment and decides he can no longer afford it.

“When someone’s financial circumstances change, they often let me know by proposing we meet less often, for example, every other week,” Dr. Reidbord wrote. “I ask to hear more and often offer to adjust my fee to allow weekly meetings to continue.”

Not all patients pay for psychiatric services, and that may make the discussion even harder. When psychiatrists participate with insurance, the patients are responsible for paying only their deductible and then a copay. The patients may unexpectedly be billed for the entire fee if their insurance terminates, or if it does not pay for a submitted claim. And patients who carry public insurance may be seen at sites where there is no out-of-pocket cost to the patient; salaried clinicians often never know if the insurance has paid. In both of these settings, finances are usually discussed with administrative personnel and not with clinical staff.

Anthony Massey, MD, is founder of Maryland’s Gladstone Psychiatry and Wellness. The group is a multidisciplinary organization, and the clinicians participate with employer-based commercial health insurances. The group accepts payment directly from the insurer, and the patient is responsible for payment of the deductible and a copay.

“We try to understand what someone owes before the first appointment. We do an eligibility check online, and we ask for payment at the time of the appointment,” Massey explained. “Sometimes the insurance changes and we don’t know, or sometimes a patient comes to the appointment without the copay. We try to work with people, but if someone builds up a balance over $500, we tell them they can’t be seen here until it’s paid down. We’ll give patients a 30-day prescription and the names of other psychiatrists who accept insurance, but we don’t keep seeing people who don’t pay for their treatment.”

In all medical settings, unpaid bills present a problem, and while most psychiatrists have a method to deal with these issues, there is no perfect answer for every doctor in every situation. There is this tension between wanting to be kind and understanding of the hardships that people have whether those hardships result from life circumstances or from their own choices and behaviors, and of our own need to make the living we feel we deserve and to pay our own bills.

“The only advice I’d give other psychiatrists is to catch it early,” Reidbord said. “Have a policy that feels fair – payment before each session, payment just after each session, payment soon after receiving a monthly itemized statement, whatever seems right to you – and stick with it. If a patient doesn’t pay according to your clearly stated policy, explore it right away. Remember that pragmatic issues like poor budgeting or unexpected expenses are just as likely as intrapsychic conflict and ‘acting out.’ Both should be considered.”

I wish I could say that in the decades since I treated Mr. A that no patients have ever failed to pay their professional fees and that I have perfectly mastered my own issues with money as it pertains to professional fees. While the vast majority of patients do pay, there are still occasional circumstances in which someone’s financial circumstances change, or very rarely where someone ends his treatment without paying for the last few sessions.
 

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016) and has a private practice in Baltimore. Patient details were altered to preserve confidentiality.

Editor’s note: This is the second in a series of articles by Dr. Miller about challenges in outpatient psychiatry.

Mr. A lived a life that seemed glamorous to me. There were lunches with professional athletes, swank social events, and designer everything from clothes to cars. It was a world that I was not familiar with, and while I knew my patient worried about money, it seemed he had it. When he started therapy with me, Mr. A came to every session with a check. At some point, I realized that I had missed a switch in his mood. Despite his therapeutic level of lithium, Mr. A had become manic, and the expression of this mania took the form of even more spending. What started as an exciting lifestyle suddenly became tens of thousands of dollars of debt. I felt guilty that I initially did not see this as pathology, and as a young psychiatrist, I sought consultation with an older and wiser mentor.

After discussing the case, the consulting psychiatrist said to me, “Make sure you get paid; these cases are difficult.” In fact, in the midst of the chaos, Mr. A had stopped bringing a check to the sessions. I sent monthly statements, and they went unpaid. He didn’t have the money for his living expenses and I let this go on without addressing it for much too long. Soon, Mr. A’s debt to me was just one more stress in his life and while I knew I would not pursue reimbursement through legal channels, I did encourage him to find a psychiatrist who was in his insurance network, something he did not want to do. I was too embarrassed to tell the consulting psychiatrist that Mr. A had already accrued well over a thousand dollars in unpaid professional fees. In my mind, I was offering pro bono care because the patient’s financial circumstances had changed, and because I felt guilty that I had not recognized this as mania sooner.

In a 2011 Shrink Rap blog post, Jesse Hellman, MD, a psychiatrist in private practice in Towson, Md., wrote about the meaning of payment in psychotherapy:

“Money is something loaded with meaning to most people. What does it mean that the patient forgets to pay? Does it mean ‘if you really cared about me you would not charge me’? Is it a reflection of anger for something that occurred in the last session? Is it a displacement of feelings from something else (‘my boss didn’t give me the raise I expected’)? Is it completely inadvertent (Freud famously said ‘Sometimes a cigar is only a cigar’)?”

There are so many possibilities, and the psychodynamic therapist wants to understand them. How the patient relates to the therapist is some part of how he relates to others. The patient hopefully starts to watch his own actions and attitudes and also tries to understand them. A nonjudgmental stance helps the patient do this.

The therapist himself needs to be comfortable dealing with the subject of money. Sometimes beginning physicians fluctuate between feeling they are too inexperienced to be paid and feeling that they deserve anything they ask. We physicians might even (unfortunately) take on the attitudes of the insurance companies themselves (“Identification with the Aggressor”).

The blog post was flooded with comments –120 in total, and more comments than any other single Shrink Rap post received for the blog’s 12-year run.

Steven Reidbord, MD, is a psychiatrist in private practice in San Francisco and also a blogger. Dr. Reidbord conversed with me through email about patients who don’t pay.

“In years past, I’ve had a few patients who met with me a few times, always ‘forgetting’ their payment and offering it ‘next time,’ until after three or four sessions, I refused to see them. I always wondered what such patients were thinking, as obviously this arrangement wouldn’t last long. Did they tell themselves they’d pay me at some point, in effect fooling themselves? Was it conscious theft of my services? A couple years ago, I started accepting charge cards, and perhaps as a result, this hasn’t happened. While it’s always useful to consider individual dynamics in explaining such behavior, it’s also important to consider normative psychology: Make it easier to pay, and more people will.”

While payment for out-of-network services is often clear cut – the patients pay and then requests reimbursement from their insurer – the logistics often are confusing for the patient. He or she may believe that she has excellent coverage, only to learn that the out-of-network deductible is very high, or that reimbursement is based on “usual and customary fees” that are much lower than his psychiatrist’s fees. Sometimes people take on the cost of psychiatric care and discover that it costs more than they assumed, or they have a change in their financial circumstances, as my patient did. Sometimes a parent is paying for treatment and decides he can no longer afford it.

“When someone’s financial circumstances change, they often let me know by proposing we meet less often, for example, every other week,” Dr. Reidbord wrote. “I ask to hear more and often offer to adjust my fee to allow weekly meetings to continue.”

Not all patients pay for psychiatric services, and that may make the discussion even harder. When psychiatrists participate with insurance, the patients are responsible for paying only their deductible and then a copay. The patients may unexpectedly be billed for the entire fee if their insurance terminates, or if it does not pay for a submitted claim. And patients who carry public insurance may be seen at sites where there is no out-of-pocket cost to the patient; salaried clinicians often never know if the insurance has paid. In both of these settings, finances are usually discussed with administrative personnel and not with clinical staff.

Anthony Massey, MD, is founder of Maryland’s Gladstone Psychiatry and Wellness. The group is a multidisciplinary organization, and the clinicians participate with employer-based commercial health insurances. The group accepts payment directly from the insurer, and the patient is responsible for payment of the deductible and a copay.

“We try to understand what someone owes before the first appointment. We do an eligibility check online, and we ask for payment at the time of the appointment,” Massey explained. “Sometimes the insurance changes and we don’t know, or sometimes a patient comes to the appointment without the copay. We try to work with people, but if someone builds up a balance over $500, we tell them they can’t be seen here until it’s paid down. We’ll give patients a 30-day prescription and the names of other psychiatrists who accept insurance, but we don’t keep seeing people who don’t pay for their treatment.”

In all medical settings, unpaid bills present a problem, and while most psychiatrists have a method to deal with these issues, there is no perfect answer for every doctor in every situation. There is this tension between wanting to be kind and understanding of the hardships that people have whether those hardships result from life circumstances or from their own choices and behaviors, and of our own need to make the living we feel we deserve and to pay our own bills.

“The only advice I’d give other psychiatrists is to catch it early,” Reidbord said. “Have a policy that feels fair – payment before each session, payment just after each session, payment soon after receiving a monthly itemized statement, whatever seems right to you – and stick with it. If a patient doesn’t pay according to your clearly stated policy, explore it right away. Remember that pragmatic issues like poor budgeting or unexpected expenses are just as likely as intrapsychic conflict and ‘acting out.’ Both should be considered.”

I wish I could say that in the decades since I treated Mr. A that no patients have ever failed to pay their professional fees and that I have perfectly mastered my own issues with money as it pertains to professional fees. While the vast majority of patients do pay, there are still occasional circumstances in which someone’s financial circumstances change, or very rarely where someone ends his treatment without paying for the last few sessions.
 

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016) and has a private practice in Baltimore. Patient details were altered to preserve confidentiality.

Editor’s note: This is the second in a series of articles by Dr. Miller about challenges in outpatient psychiatry.

Mr. A lived a life that seemed glamorous to me. There were lunches with professional athletes, swank social events, and designer everything from clothes to cars. It was a world that I was not familiar with, and while I knew my patient worried about money, it seemed he had it. When he started therapy with me, Mr. A came to every session with a check. At some point, I realized that I had missed a switch in his mood. Despite his therapeutic level of lithium, Mr. A had become manic, and the expression of this mania took the form of even more spending. What started as an exciting lifestyle suddenly became tens of thousands of dollars of debt. I felt guilty that I initially did not see this as pathology, and as a young psychiatrist, I sought consultation with an older and wiser mentor.

After discussing the case, the consulting psychiatrist said to me, “Make sure you get paid; these cases are difficult.” In fact, in the midst of the chaos, Mr. A had stopped bringing a check to the sessions. I sent monthly statements, and they went unpaid. He didn’t have the money for his living expenses and I let this go on without addressing it for much too long. Soon, Mr. A’s debt to me was just one more stress in his life and while I knew I would not pursue reimbursement through legal channels, I did encourage him to find a psychiatrist who was in his insurance network, something he did not want to do. I was too embarrassed to tell the consulting psychiatrist that Mr. A had already accrued well over a thousand dollars in unpaid professional fees. In my mind, I was offering pro bono care because the patient’s financial circumstances had changed, and because I felt guilty that I had not recognized this as mania sooner.

In a 2011 Shrink Rap blog post, Jesse Hellman, MD, a psychiatrist in private practice in Towson, Md., wrote about the meaning of payment in psychotherapy:

“Money is something loaded with meaning to most people. What does it mean that the patient forgets to pay? Does it mean ‘if you really cared about me you would not charge me’? Is it a reflection of anger for something that occurred in the last session? Is it a displacement of feelings from something else (‘my boss didn’t give me the raise I expected’)? Is it completely inadvertent (Freud famously said ‘Sometimes a cigar is only a cigar’)?”

There are so many possibilities, and the psychodynamic therapist wants to understand them. How the patient relates to the therapist is some part of how he relates to others. The patient hopefully starts to watch his own actions and attitudes and also tries to understand them. A nonjudgmental stance helps the patient do this.

The therapist himself needs to be comfortable dealing with the subject of money. Sometimes beginning physicians fluctuate between feeling they are too inexperienced to be paid and feeling that they deserve anything they ask. We physicians might even (unfortunately) take on the attitudes of the insurance companies themselves (“Identification with the Aggressor”).

The blog post was flooded with comments –120 in total, and more comments than any other single Shrink Rap post received for the blog’s 12-year run.

Steven Reidbord, MD, is a psychiatrist in private practice in San Francisco and also a blogger. Dr. Reidbord conversed with me through email about patients who don’t pay.

“In years past, I’ve had a few patients who met with me a few times, always ‘forgetting’ their payment and offering it ‘next time,’ until after three or four sessions, I refused to see them. I always wondered what such patients were thinking, as obviously this arrangement wouldn’t last long. Did they tell themselves they’d pay me at some point, in effect fooling themselves? Was it conscious theft of my services? A couple years ago, I started accepting charge cards, and perhaps as a result, this hasn’t happened. While it’s always useful to consider individual dynamics in explaining such behavior, it’s also important to consider normative psychology: Make it easier to pay, and more people will.”

While payment for out-of-network services is often clear cut – the patients pay and then requests reimbursement from their insurer – the logistics often are confusing for the patient. He or she may believe that she has excellent coverage, only to learn that the out-of-network deductible is very high, or that reimbursement is based on “usual and customary fees” that are much lower than his psychiatrist’s fees. Sometimes people take on the cost of psychiatric care and discover that it costs more than they assumed, or they have a change in their financial circumstances, as my patient did. Sometimes a parent is paying for treatment and decides he can no longer afford it.

“When someone’s financial circumstances change, they often let me know by proposing we meet less often, for example, every other week,” Dr. Reidbord wrote. “I ask to hear more and often offer to adjust my fee to allow weekly meetings to continue.”

Not all patients pay for psychiatric services, and that may make the discussion even harder. When psychiatrists participate with insurance, the patients are responsible for paying only their deductible and then a copay. The patients may unexpectedly be billed for the entire fee if their insurance terminates, or if it does not pay for a submitted claim. And patients who carry public insurance may be seen at sites where there is no out-of-pocket cost to the patient; salaried clinicians often never know if the insurance has paid. In both of these settings, finances are usually discussed with administrative personnel and not with clinical staff.

Anthony Massey, MD, is founder of Maryland’s Gladstone Psychiatry and Wellness. The group is a multidisciplinary organization, and the clinicians participate with employer-based commercial health insurances. The group accepts payment directly from the insurer, and the patient is responsible for payment of the deductible and a copay.

“We try to understand what someone owes before the first appointment. We do an eligibility check online, and we ask for payment at the time of the appointment,” Massey explained. “Sometimes the insurance changes and we don’t know, or sometimes a patient comes to the appointment without the copay. We try to work with people, but if someone builds up a balance over $500, we tell them they can’t be seen here until it’s paid down. We’ll give patients a 30-day prescription and the names of other psychiatrists who accept insurance, but we don’t keep seeing people who don’t pay for their treatment.”

In all medical settings, unpaid bills present a problem, and while most psychiatrists have a method to deal with these issues, there is no perfect answer for every doctor in every situation. There is this tension between wanting to be kind and understanding of the hardships that people have whether those hardships result from life circumstances or from their own choices and behaviors, and of our own need to make the living we feel we deserve and to pay our own bills.

“The only advice I’d give other psychiatrists is to catch it early,” Reidbord said. “Have a policy that feels fair – payment before each session, payment just after each session, payment soon after receiving a monthly itemized statement, whatever seems right to you – and stick with it. If a patient doesn’t pay according to your clearly stated policy, explore it right away. Remember that pragmatic issues like poor budgeting or unexpected expenses are just as likely as intrapsychic conflict and ‘acting out.’ Both should be considered.”

I wish I could say that in the decades since I treated Mr. A that no patients have ever failed to pay their professional fees and that I have perfectly mastered my own issues with money as it pertains to professional fees. While the vast majority of patients do pay, there are still occasional circumstances in which someone’s financial circumstances change, or very rarely where someone ends his treatment without paying for the last few sessions.
 

Dr. Miller is the coauthor with Annette Hanson, MD, of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016) and has a private practice in Baltimore. Patient details were altered to preserve confidentiality.

DENVER – Among patients with facial erythema associated with erythrotelangiectatic rosacea, combining a long-pulsed 532 nm laser with daily application of a topical skin care regimen achieved equivalent to superior results in fewer treatments, compared with long-pulsed laser treatment alone.

The findings come from a pilot trial that Brian S. Biesman, MD, presented at the annual conference of the American Society for Laser Medicine and Surgery.

“Vascular laser therapy is the standard of care for reduction of facial erythema associated with erythrotelangiectatic rosacea,” said Dr. Biesman, an oculofacial plastic surgeon who practices in Nashville, Tenn. “The question was, if we combine topicals plus laser, can we get an enhanced outcome relative to laser treatment alone?”

To find out, he and his colleagues conducted a blinded, controlled prospective study of 30 subjects with mild to moderate erythrotelangiectatic rosacea who were evenly split into two groups. Those in group 1 received three treatments with the Excel V 532 nm long-pulsed laser by Cutera. Those in group 2 received two laser treatments with the Excel V long-pulsed 532 nm long-pulsed laser plus concurrent daily use of the topical Jan Marini Skin Care Management System, which included a glycolic acid cleanser, vitamin C serum, active containing glycolic, salicylic and azelaic acids, peptide, and growth factor moisturizer and a broad-spectrum sunscreen. It also contained RosaLieve, a proprietary redness-reducing complex.

The researchers performed laser treatments at 4-week intervals and evaluated subjects at baseline, 4, 8, and 12 weeks by physician and subject self-assessment using 5-point (0-4) standardized scales: the Clinician Erythema Assessment (CEA) and patient self-assessment as well as a dermatology Quality of Life Assessment. In both treatment groups, reduction in facial erythema as assessed by CEA and patient self-assessment showed statistically significant improvement at all measured intervals. Specifically, average CEA scores improved from 3.00 to 1.87 among patients in group 1, and from 3.07 to 1.64 among those in group 2. “These were both statistically significant from baseline,” Dr. Biesman said. “What does it really say? The laser plus topical was superior to the laser-only treatment at all measured intervals. I didn’t expect to see that. There was continued improvement noted from week 8 to week 12. That was more of a trend; it was not statistically significant. There were no complications or adverse reactions in either group. The study data indicate that best results may be achieved with a combination of laser and home care.”

He acknowledged certain limitations of the study, including its small sample size and relatively short course of follow-up. “We didn’t have standardization of topical therapy in the laser-only group,” Dr. Biesman said. “Those patients were told to use their usual topical regimen. They were not allowed to use retinoids. We also didn’t have a control arm.”

He disclosed that he has received grant funding from Jan Marini Skin Research and Cutera.

[email protected]

DENVER – Among patients with facial erythema associated with erythrotelangiectatic rosacea, combining a long-pulsed 532 nm laser with daily application of a topical skin care regimen achieved equivalent to superior results in fewer treatments, compared with long-pulsed laser treatment alone.

The findings come from a pilot trial that Brian S. Biesman, MD, presented at the annual conference of the American Society for Laser Medicine and Surgery.

“Vascular laser therapy is the standard of care for reduction of facial erythema associated with erythrotelangiectatic rosacea,” said Dr. Biesman, an oculofacial plastic surgeon who practices in Nashville, Tenn. “The question was, if we combine topicals plus laser, can we get an enhanced outcome relative to laser treatment alone?”

To find out, he and his colleagues conducted a blinded, controlled prospective study of 30 subjects with mild to moderate erythrotelangiectatic rosacea who were evenly split into two groups. Those in group 1 received three treatments with the Excel V 532 nm long-pulsed laser by Cutera. Those in group 2 received two laser treatments with the Excel V long-pulsed 532 nm long-pulsed laser plus concurrent daily use of the topical Jan Marini Skin Care Management System, which included a glycolic acid cleanser, vitamin C serum, active containing glycolic, salicylic and azelaic acids, peptide, and growth factor moisturizer and a broad-spectrum sunscreen. It also contained RosaLieve, a proprietary redness-reducing complex.

The researchers performed laser treatments at 4-week intervals and evaluated subjects at baseline, 4, 8, and 12 weeks by physician and subject self-assessment using 5-point (0-4) standardized scales: the Clinician Erythema Assessment (CEA) and patient self-assessment as well as a dermatology Quality of Life Assessment. In both treatment groups, reduction in facial erythema as assessed by CEA and patient self-assessment showed statistically significant improvement at all measured intervals. Specifically, average CEA scores improved from 3.00 to 1.87 among patients in group 1, and from 3.07 to 1.64 among those in group 2. “These were both statistically significant from baseline,” Dr. Biesman said. “What does it really say? The laser plus topical was superior to the laser-only treatment at all measured intervals. I didn’t expect to see that. There was continued improvement noted from week 8 to week 12. That was more of a trend; it was not statistically significant. There were no complications or adverse reactions in either group. The study data indicate that best results may be achieved with a combination of laser and home care.”

He acknowledged certain limitations of the study, including its small sample size and relatively short course of follow-up. “We didn’t have standardization of topical therapy in the laser-only group,” Dr. Biesman said. “Those patients were told to use their usual topical regimen. They were not allowed to use retinoids. We also didn’t have a control arm.”

He disclosed that he has received grant funding from Jan Marini Skin Research and Cutera.

[email protected]

DENVER – Among patients with facial erythema associated with erythrotelangiectatic rosacea, combining a long-pulsed 532 nm laser with daily application of a topical skin care regimen achieved equivalent to superior results in fewer treatments, compared with long-pulsed laser treatment alone.

The findings come from a pilot trial that Brian S. Biesman, MD, presented at the annual conference of the American Society for Laser Medicine and Surgery.

“Vascular laser therapy is the standard of care for reduction of facial erythema associated with erythrotelangiectatic rosacea,” said Dr. Biesman, an oculofacial plastic surgeon who practices in Nashville, Tenn. “The question was, if we combine topicals plus laser, can we get an enhanced outcome relative to laser treatment alone?”

To find out, he and his colleagues conducted a blinded, controlled prospective study of 30 subjects with mild to moderate erythrotelangiectatic rosacea who were evenly split into two groups. Those in group 1 received three treatments with the Excel V 532 nm long-pulsed laser by Cutera. Those in group 2 received two laser treatments with the Excel V long-pulsed 532 nm long-pulsed laser plus concurrent daily use of the topical Jan Marini Skin Care Management System, which included a glycolic acid cleanser, vitamin C serum, active containing glycolic, salicylic and azelaic acids, peptide, and growth factor moisturizer and a broad-spectrum sunscreen. It also contained RosaLieve, a proprietary redness-reducing complex.

The researchers performed laser treatments at 4-week intervals and evaluated subjects at baseline, 4, 8, and 12 weeks by physician and subject self-assessment using 5-point (0-4) standardized scales: the Clinician Erythema Assessment (CEA) and patient self-assessment as well as a dermatology Quality of Life Assessment. In both treatment groups, reduction in facial erythema as assessed by CEA and patient self-assessment showed statistically significant improvement at all measured intervals. Specifically, average CEA scores improved from 3.00 to 1.87 among patients in group 1, and from 3.07 to 1.64 among those in group 2. “These were both statistically significant from baseline,” Dr. Biesman said. “What does it really say? The laser plus topical was superior to the laser-only treatment at all measured intervals. I didn’t expect to see that. There was continued improvement noted from week 8 to week 12. That was more of a trend; it was not statistically significant. There were no complications or adverse reactions in either group. The study data indicate that best results may be achieved with a combination of laser and home care.”

He acknowledged certain limitations of the study, including its small sample size and relatively short course of follow-up. “We didn’t have standardization of topical therapy in the laser-only group,” Dr. Biesman said. “Those patients were told to use their usual topical regimen. They were not allowed to use retinoids. We also didn’t have a control arm.”

He disclosed that he has received grant funding from Jan Marini Skin Research and Cutera.

[email protected]

DENVER – A device that provides electromagnetic stimulation to muscles is being investigated as a way to complement noninvasive body contouring.

The device, known as CoolTone, is being developed by Allergan and uses high-powered coil electromagnetic stimulation applicators to induce eddy currents in the muscle tissue. CoolTone is pending Food and Drug Administration clearance and is not yet commercially available.

“Fat reduction is just one part of body contouring,” Mathew M. Avram, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “You have skin, fat, and muscle. More and more we’re targeting all three areas for patients’ best body contouring outcomes.”

According to Dr. Avram, director of the Massachusetts General Hospital Dermatology Laser & Cosmetic Center, Boston, CoolTone provides high-frequency electromagnetic muscle stimulation that triggers muscle contractions that cannot be achieved by normal exercise to increase muscle mass and strength. “You’re doing super physiological amounts of contractions with this stimulation – the equivalent of doing thousands of sit-ups, if you’re treating the abdomen,” he said. “It strengthens, tones, and firms muscles in abdomen, buttocks, arms, and legs. There is a history of this type of technology for athletes and other indications in physical therapy.”

The current FDA clearance for a predicate electromagnetic stimulation system for muscle conditioning is for the abdomen, buttocks, thighs, and arms. “This is for improvement of abdominal tone, strengthening of the abdominal muscles, and development of a firmer abdomen,” said Dr. Avram, who also is director of dermatologic surgery at Mass General. “It’s for strengthening, toning, and firming of buttocks and thighs, and for improvement of muscle tone and firmness, and for strengthening muscle in arms.”

The electrical current induced by the CoolTone device flows readily into muscle and not into fat, he continued. This brings the current to nearby motor nerve structures that stimulate contraction once the action potential is reached. “You’re getting maximal contractions that are extreme for a full range of muscle fibers,” explained Dr. Avram, who is the immediate past president of the ASLMS. “This requires an external electrical stimulus; it’s not something you do with normal exercise. With mild exercise, only the slow-twitch muscle fibers are activated, not the fast-twitch muscle fibers. Also, the pulsing sequences are designed to preferentially excite motor nerves rather than sensory nerves. So it’s really going after the ability for you to contract your muscles as much as possible.”

Dr. Avram has received consulting fees from Merz and Alastin and holds ownership interests with ZALEA, InMode, and Cytrellis. He has served on the advisory boards for ZELTIQ Aesthetics, Soliton, Sciton, and Sienna Biopharmaceuticals, and he has intellectual property rights with Cytrellis.

[email protected]

DENVER – A device that provides electromagnetic stimulation to muscles is being investigated as a way to complement noninvasive body contouring.

The device, known as CoolTone, is being developed by Allergan and uses high-powered coil electromagnetic stimulation applicators to induce eddy currents in the muscle tissue. CoolTone is pending Food and Drug Administration clearance and is not yet commercially available.

“Fat reduction is just one part of body contouring,” Mathew M. Avram, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “You have skin, fat, and muscle. More and more we’re targeting all three areas for patients’ best body contouring outcomes.”

According to Dr. Avram, director of the Massachusetts General Hospital Dermatology Laser & Cosmetic Center, Boston, CoolTone provides high-frequency electromagnetic muscle stimulation that triggers muscle contractions that cannot be achieved by normal exercise to increase muscle mass and strength. “You’re doing super physiological amounts of contractions with this stimulation – the equivalent of doing thousands of sit-ups, if you’re treating the abdomen,” he said. “It strengthens, tones, and firms muscles in abdomen, buttocks, arms, and legs. There is a history of this type of technology for athletes and other indications in physical therapy.”

The current FDA clearance for a predicate electromagnetic stimulation system for muscle conditioning is for the abdomen, buttocks, thighs, and arms. “This is for improvement of abdominal tone, strengthening of the abdominal muscles, and development of a firmer abdomen,” said Dr. Avram, who also is director of dermatologic surgery at Mass General. “It’s for strengthening, toning, and firming of buttocks and thighs, and for improvement of muscle tone and firmness, and for strengthening muscle in arms.”

The electrical current induced by the CoolTone device flows readily into muscle and not into fat, he continued. This brings the current to nearby motor nerve structures that stimulate contraction once the action potential is reached. “You’re getting maximal contractions that are extreme for a full range of muscle fibers,” explained Dr. Avram, who is the immediate past president of the ASLMS. “This requires an external electrical stimulus; it’s not something you do with normal exercise. With mild exercise, only the slow-twitch muscle fibers are activated, not the fast-twitch muscle fibers. Also, the pulsing sequences are designed to preferentially excite motor nerves rather than sensory nerves. So it’s really going after the ability for you to contract your muscles as much as possible.”

Dr. Avram has received consulting fees from Merz and Alastin and holds ownership interests with ZALEA, InMode, and Cytrellis. He has served on the advisory boards for ZELTIQ Aesthetics, Soliton, Sciton, and Sienna Biopharmaceuticals, and he has intellectual property rights with Cytrellis.

[email protected]

DENVER – A device that provides electromagnetic stimulation to muscles is being investigated as a way to complement noninvasive body contouring.

The device, known as CoolTone, is being developed by Allergan and uses high-powered coil electromagnetic stimulation applicators to induce eddy currents in the muscle tissue. CoolTone is pending Food and Drug Administration clearance and is not yet commercially available.

“Fat reduction is just one part of body contouring,” Mathew M. Avram, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “You have skin, fat, and muscle. More and more we’re targeting all three areas for patients’ best body contouring outcomes.”

According to Dr. Avram, director of the Massachusetts General Hospital Dermatology Laser & Cosmetic Center, Boston, CoolTone provides high-frequency electromagnetic muscle stimulation that triggers muscle contractions that cannot be achieved by normal exercise to increase muscle mass and strength. “You’re doing super physiological amounts of contractions with this stimulation – the equivalent of doing thousands of sit-ups, if you’re treating the abdomen,” he said. “It strengthens, tones, and firms muscles in abdomen, buttocks, arms, and legs. There is a history of this type of technology for athletes and other indications in physical therapy.”

The current FDA clearance for a predicate electromagnetic stimulation system for muscle conditioning is for the abdomen, buttocks, thighs, and arms. “This is for improvement of abdominal tone, strengthening of the abdominal muscles, and development of a firmer abdomen,” said Dr. Avram, who also is director of dermatologic surgery at Mass General. “It’s for strengthening, toning, and firming of buttocks and thighs, and for improvement of muscle tone and firmness, and for strengthening muscle in arms.”

The electrical current induced by the CoolTone device flows readily into muscle and not into fat, he continued. This brings the current to nearby motor nerve structures that stimulate contraction once the action potential is reached. “You’re getting maximal contractions that are extreme for a full range of muscle fibers,” explained Dr. Avram, who is the immediate past president of the ASLMS. “This requires an external electrical stimulus; it’s not something you do with normal exercise. With mild exercise, only the slow-twitch muscle fibers are activated, not the fast-twitch muscle fibers. Also, the pulsing sequences are designed to preferentially excite motor nerves rather than sensory nerves. So it’s really going after the ability for you to contract your muscles as much as possible.”

Dr. Avram has received consulting fees from Merz and Alastin and holds ownership interests with ZALEA, InMode, and Cytrellis. He has served on the advisory boards for ZELTIQ Aesthetics, Soliton, Sciton, and Sienna Biopharmaceuticals, and he has intellectual property rights with Cytrellis.

[email protected]