Drug-Induced Thrombocytopenia Due to Nintedanib during Treatment of Idiopathic Pulmonary Fibrosis.

Nintedanib is a tyrosine kinase inhibitor that was approved for the treatment of patients with idiopathic pulmonary fibrosis in 2014. The most common side effect of Nintedanib is diarrhea, and thrombocytopenia is a rare side effect of Nintedanib. The exact mechanism is unknown, and the literature lacks case reports of this phenomenon. Here, we report the case of a patient who developed thrombocytopenia 12 weeks after starting treatment with Nintedanib. The patient underwent an extensive work up for infectious, hematological, autoimmune, and neoplastic diseases. The patient's thrombocytopenia resolved following cessation of Nintedanib. This case is significant as it reports a rare side effect that might have detrimental consequences if not recognized and treated timely. Additionally, the onset of thrombocytopenia was delayed, 3 months after the initiation of Nintedanib. We also highlight the various literature regarding drug-induced thrombocytopenia and explore the necessary work-up needed to exclude other potential diagnoses. We hope to advocate for multidisciplinary teams to be aware of patients with pulmonary fibrosis on Nintedanib so that this adverse effect can be recognized promptly.

Vasopressin-induced hyponatremia in an adult normotensive trauma patient: A case report.

BACKGROUND: Arginine vasopressin is a neuropeptide produced in the hypothalamus and released by the posterior pituitary gland. In addition to maintaining plasma osmolarity, under hypovolemic or hypotensive conditions, it helps maintain plasma volume through renal water reabsorption and increases systemic vascular tone. Its synthetic analogues are widely used in the intensive care unit as a continuous infusion, in addition to hospital floors as an intravenous or intranasal dose. A limited number of cases of hyponatremia in patients with septic or hemorrhagic shock have been reported previously with vasopressin. We report for the first time a normotensive patient who developed vasopressin-induced hyponatremia. CASE SUMMARY: A 39-year-old man fell off a forklift and sustained an axial load injury to his cranium. He had no history of previous trauma. Examination was normal except for motor and sensory deficits. The Imagine test showed endplate fracture at C7 and acute traumatic disc at C7 with cortical degeneration. He underwent cervical discectomy and fusion, laminectomy, and posterior instrumented fusion. After intensive care unit admission post-surgery, he developed hyponatremia of 121-124 mEq/L post phenylephrine and vasopressin infusion to maintain blood pressure maintenance. He was evaluated for syndrome of inappropriate secretion of antidiuretic hormone, hypothyroid, adrenal-induced, or diuretic-induced hyponatremia. At the end of extensive evaluation for the underlying cause of hyponatremia, vasopressin was discontinued. He was also put on fluid restriction, given exogenous desmopressin, and a dextrose 5% in water infusion to prevent osmotic demyelination syndrome caused by sodium overcorrection which improved his sodium level to 135 mmol/L. CONCLUSION: The presentation of vasopressin-induced hyponatremia is uncommon in normotensive patients, and the most difficult aspect of this condition is determining the underlying cause of hyponatremia. Our case illustrates that, considering the vast differential diagnosis of hyponatremia in hospitalized patients, both hospitalists and intensivists should be aware of this serious complication of vasopressin therapy.

Transient Complete Blindness Due to Metformin-Associated Lactic Acidosis (MALA) Reversed with Hemodialysis.

BACKGROUND Metformin-associated lactic acidosis (MALA) is a relatively rare adverse effect of metformin therapy. It usually occurs in patients with metformin overdose or in those with underlying acute and/or chronic conditions resulting in impaired lactate metabolism. Among these, patients with acute kidney injury, heart failure, sepsis, and cirrhosis are the most vulnerable to MALA, even in the setting of appropriate therapy. The most common symptoms of MALA include nausea, vomiting, diarrhea, encephalopathy, hypothermia, respiratory failure, and hypotension. Blindness is a dramatic symptom that has been rarely reported with MALA. CASE REPORT We report a case of 78-year-old woman with history of type 2 diabetes mellitus with nephropathy for which she was treated with metformin and insulin. She developed nausea, non-bloody emesis, and watery diarrhea, which led to dehydration, anion gap metabolic acidosis due to hyperlactatemia, and acute kidney injury (AKI). She was hospitalized for i.v. hydration and further management when she suddenly developed blindness. The diagnostic work-up ruled out central causes and her symptoms resolved briefly after continuous renal replacement therapy (CRRT) was initiated, confirming the diagnosis of MALA. CONCLUSIONS By reporting this case, we wish to increase awareness about MALA symptoms, its diagnosis, and the importance of early recognition and initiation of treatment among clinicians involved in the care of patients with chronic kidney disease (CKD) who take metformin for diabetes mellitus. Although rare, this metformin adverse effect can present dramatically and can be distressing for both patient and treating team.

Acute exacerbation of interstitial lung disease in the intensive care unit.

Acute exacerbations of interstitial lung disease (AE-ILD) represent an acute, frequent and often highly morbid event in the disease course of ILD patients. Admission in the intensive care unit (ICU) is very common and the need for mechanical ventilation arises early. While non-invasive ventilation has shown promise in staving off intubation in selected patients, it is unclear whether mechanical ventilation can alter the exacerbation course unless it is a bridge to lung transplantation. Risk stratification using clinical and radiographic findings, and early palliative care involvement, are important in ICU care. In this review, we discuss many of the pathophysiological aspects of AE-ILD and raise the hypothesis that ventilation strategies used in acute respiratory distress syndrome might be implemented in AE-ILD. We present possible decision-making and management algorithms that can be used by the intensivist when caring for these patients.

Challenges in the Diagnosis and Management of Fibrotic Hypersensitivity Pneumonitis: A Practical Review of Current Approaches.

Recent advances in fibrotic hypersensitivity pneumonitis include improved diagnostic guidance, systematic assessments of immunosuppressive therapy, and the recent availability of antifibrotic therapy (nintedanib) for those with progressive disease. A standardized approach to diagnosis may lead to better inclusion criteria for future therapeutic protocols and delineation of disease or treatment response predictors for real-world management. This review will highlight current diagnostic and treatment challenges and remaining knowledge gaps or areas of uncertainty, with a practical overview of supporting evidence and its clinical implications. Exposure history, serologic testing for antigen sensitivity, bronchoalveolar lavage lymphocytosis, histopathology, and radiologic findings will be covered in the diagnosis section, with immunosuppression, antifibrotic therapy, lung transplantation, and disease prognosis in the treatment and management section.

Lung Cancer Risk among Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Rationale: Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is mixed. Whether asthma-COPD overlap (ACO) is associated with lung cancer has not been studied. Objectives: We aimed to compare lung cancer risk among patients with ACO versus COPD and other conditions associated with airway obstruction. Methods: We studied 13,939 smokers from the National Lung Cancer Screening Trial who had baseline spirometry and used spirometric indices and history of childhood asthma to categorize participants into five specific airway disease subgroups. We used Poisson regression to compare unadjusted and adjusted lung cancer risk. Results: The incidence rate of lung cancer per 1,000 person-years was as follows: ACO, 13.2 (95% confidence interval [CI], 8.1-21.5); COPD, 11.7 (95% CI, 10.5-13.1); asthmatic smokers, 1.8 (95% CI, 0.6-5.4); Global Initiative for Chronic Obstructive Lung Disease-Unclassified, 7.7 (95% CI, 6.4-9.2); and normal spirometry smokers, 4.1 (95% CI, 3.5-4.8). Patients with ACO had increased adjusted risk of lung cancer compared with patients with asthma (incidence rate ratio [IRR], 4.5; 95% CI, 1.3-15.8) and normal spirometry smokers (IRR, 2.3; 95% CI, 1.3-4.2) in models adjusting for other risk factors. Adjusted lung cancer incidence in patients with ACO and COPD were not found to be different (IRR, 1.2; 95% CI, 0.7-2.1). Conclusions: The risk of lung cancer among patients with ACO is similar to those with COPD and higher than other groups of smokers. These results provide further evidence that COPD, with or without a history of childhood asthma, is an independent risk factor for lung cancer.

Assessing the association of diabetes with lung cancer risk.

BACKGROUND: Diabetes is a well-established risk factor for many cancers, but its relationship with lung cancer incidence remains unclear. In this study, we aimed to assess if diabetes is independently associated with lung cancer risk and histology subtype among participants in a screening study. METHODS: In a retrospective cohort study using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) study, we assessed the association of self-reported diabetes with lung cancer incidence using Poisson regression while adjusting for other established risk factors in the PLCOM2012, a validated lung cancer prediction model. The adjusted association of diabetes and lung cancer cell type was evaluated using nominal regression. Stratified analyses were also conducted according to sex, smoking history, and body mass index categories. RESULTS: Overall, 140,395 participants were included in our analysis. Diabetes was not significantly associated with lung cancer incidence [incidence rate ratio (IRR): 1.03, 95% confidence interval (CI): 0.91-1.17]. Similarly, stratified analyses also did not show significant associations between diabetes and lung cancer risk (all P values >0.05). We found no significant difference in the distribution of lung cancer histology in participants with vs. without diabetes (P=0.30). CONCLUSIONS: Diabetes was not an independent risk factor for lung cancer in a large cohort of PLCO participants. We did not observe differences in histology according to diabetes status. These results suggest that patients with diabetes do not need more aggressive lung cancer screening. Future research including more detailed metabolic parameters may further elucidate the relationship between metabolic disease and lung cancer risk.

Obstructive Sleep Apnea and Pain Intensity in Young Adults.

Rationale: Prior research studies on the association of obstructive sleep apnea (OSA) and pain intensity have examined older patients; there is a need to understand the relationship between OSA and pain intensity among younger adults.Objectives: To examine whether young adults with diagnosed OSA are more likely to report higher pain intensity compared with those without OSA.Methods: We conducted a cross-sectional analysis of a cohort study of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans who had at least one visit to a Veterans Health Administration primary care clinic between 2001 and 2014. OSA was identified using one inpatient or two outpatient International Classification of Diseases, Ninth Revision codes from electronic medical records. Average pain intensity (based on the self-reported 0-10 numeric rating scale over a 12-month period) was categorized as no pain/mild (0-3; no pain) and moderate/severe (4-10; significant pain). Covariates included age, sex, education, race, mental health diagnoses, headache diagnoses, pain diagnoses, hypertension, diabetes, body mass index, and smoking status. Multivariate logistic regression models were used, and multiple imputation was performed to generate values for missing variables.Results: We identified 858,226 young adults (mean age 30 yr [SD = 7]), of whom 91,244 (10.6%) had a diagnosis of OSA and 238,587 (27.8%) reported moderate/severe pain for the 12-month average. with young adults without OSA, those with OSA were more likely to report moderate/severe pain intensity (adjusted odds ratio, 1.09; 95% confidence interval, 1.08-1.11) even after controlling for covariates.Conclusions: We found that young adults with OSA have greater odds of comorbid moderate/severe pain. Because of the high prevalence of chronic pain in younger adults, this study highlights the need to understand the impact of OSA diagnosis and treatment on pain intensity. Future work is needed to determine the role of effective OSA treatment on pain intensity over time in these young adults.

Iatrogenic Nontraumatic CPAP-Induced Pneumocephalus in a Patient With Meningitis.

ABSTRACT: Pneumocephalus, or air within the cranium, can be caused by trauma, intracranial infections, or tumors, and can also occur as a complication of neurosurgery and lumbar puncture. Continuous positive airway pressure (CPAP) therapy can precipitate or worsen pneumocephalus in cases of known head trauma. However, nontraumatic pneumocephalus being caused by CPAP is a highly unexpected clinical event. We describe a case of a patient who presented with meningitis due to an atypical organism that usually resides in the oral cavity, and who developed nontraumatic pneumocephalus in the hospital due to CPAP therapy. The underlying cause, a cerebrospinal fluid leak, was likely the mediator for both pathologies. In the setting of the increasing prevalence of obstructive sleep apnea, physicians can benefit from being aware of this atypical presentation of meningitis and atypical complication of CPAP therapy.

Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure.

BACKGROUND AND OBJECTIVES: Diuretic resistance can limit successful decongestion of patients with heart failure. Because loop diuretics tightly bind albumin, low serum albumin and high urine albumin can theoretically limit diuretic delivery to the site of action. However, it is unknown if this represents a clinically relevant mechanism of diuretic resistance in human heart failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 208 outpatients with heart failure at the Yale Transitional Care Center undergoing diuretic treatment were studied. Blood and urine chemistries were collected at baseline and 1.5 hours postdiuretic administration. Urine diuretic levels were normalized to urine creatinine and adjusted for diuretic dose administered, and diuretic efficiency was calculated as sodium output per doubling of the loop diuretic dose. Findings were validated in an inpatient heart failure cohort (n=60). RESULTS: Serum albumin levels in the outpatient cohort ranged from 2.4 to 4.9 g/dl, with a median of 3.7 g/dl (interquartile range, 3.5-4.1). Serum albumin had no association with urinary diuretic delivery (r=-0.05; P=0.52), but higher levels weakly correlated with better diuretic efficiency (r=0.17; P=0.02). However, serum albumin inversely correlated with systemic inflammation as assessed by plasma IL-6 (r=-0.35; P<0.001), and controlling for IL-6 eliminated the diuretic efficiency-serum albumin association (r=0.12; P=0.12). In the inpatient cohort, there was no association between serum albumin and urinary diuretic excretion (r=0.15; P=0.32) or diuretic efficiency (r=-0.16; P=0.25). In the outpatient cohort, 39% of patients had microalbuminuria, and 18% had macroalbuminuria. There was no correlation between albuminuria and diuretic efficiency after adjusting for kidney function (r=-0.02; P=0.89). Results were similar in the inpatient cohort. CONCLUSIONS: Serum albumin levels were not associated with urinary diuretic excretion, and urinary albumin levels were not associated with diuretic efficiency.

The Association of Obstructive Sleep Apnea and Pain Outcomes in Adults: A Systematic Review.

Objective: The specific link between obstructive sleep apnea (OSA) and pain is unknown, but it has been hypothesized that OSA patients are hyperalgesic because of fragmented sleep and hypoxemia that enhance sensitivity to pain, promote inflammation, and increase spontaneous pain. We conducted a systematic review of the literature assessing whether OSA is a risk factor for subjective pain intensity and experimental pain tolerance and threshold. Design/Participants: A search of published studies in English in MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews from database inception through May 2017 was performed. Search terms included "sleep apnea," "continuous positive airway pressure," "CPAP," "pain," and "chronic pain." Methods: We included any study that reported an association between OSA or polysomnogram assessments with pain outcomes or reported the effect of CPAP on pain outcomes. Controlled studies, cohort studies, and case-control studies were included. Results: We identified 448 studies from PubMed and 959 studies from Embase, giving a combined 1,333 studies after removing duplicates. After detailed selection, 28 articles were reviewed in full and 12 met study inclusion criteria. Whereas several studies found an association between OSA and pain intensity or experimental pain, there was considerable variability among study outcomes. Delivery of CPAP may improve pain and decrease opioid use, although the exact nature of the relationship between pain and the various pathophysiologic components of OSA is unclear. Conclusions: This systematic review summarizes the current evidence for the association of OSA and pain outcomes. Further research is needed to identify the differential effects of nocturnal hypoxemia and fragmented sleep on pain intensity. Clinicians might consider screening patients with chronic pain for OSA.

Weakness and pain in arms and legs · dark urine · history of vertebral osteomyelitis · Dx?

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious usclerelated syndrome. Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold. The trigger for our patient's statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.

Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response.

Implantation of biomaterials elicits a foreign body response characterized by fusion of macrophages to form foreign body giant cells and fibrotic encapsulation. Studies of the macrophage polarization involved in this response have suggested that alternative (M2) activation is associated with more favorable outcomes. Here we investigated this process in vivo by implanting mixed cellulose ester filters or polydimethylsiloxane disks in the peritoneal cavity of wild-type (WT) and monocyte chemoattractant protein-1 (MCP-1) knockout mice. We analyzed classical (M1) and alternative (M2) gene expression via quantitative polymerase chain reaction, immunohistochemistry and enzyme-linked immunosorbent assay in both non-adherent cells isolated by lavage and implant-adherent cells. Our results show that macrophages undergo unique activation that displays features of both M1 and M2 polarization including induction of tumor necrosis factor α (TNF), which induces the expression and nuclear translocation of p50 and RelA determined by immunofluorescence and Western blot. Both processes were compromised in fusion-deficient MCP-1 KO macrophages in vitro and in vivo. Furthermore, inclusion of BAY 11-7028, an inhibitor of NFκB activation, reduced nuclear translocation of RelA and fusion in WT macrophages. Our studies suggest that peritoneal implants elicit a unique macrophage polarization phenotype leading to induction of TNF and activation of the NFκB pathway.

Lack of TNF-α-induced MMP-9 production and abnormal E-cadherin redistribution associated with compromised fusion in MCP-1-null macrophages.

Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wild-type and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-α (TNF-α) production and abnormal subcellular redistribution of E-cadherin and ß-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-α caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/ß-catenin and one for MCP-1, TNF-α, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/ß-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-α and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.