A 44-year-old female with no known medical history is admitted to the intensive care unit (ICU) with septic shock, presumably from influenza. She is treated with mechanical ventilation, vasopressors, and broad-spectrum antimicrobials including oseltamivir, vancomycin, cefepime, flagyl, and azithromycin. Despite 5 days of treatment, she fails to improve. She has persistent fever to 38.9°C and requires norepinephrine and vasopressin to treat hypotension. Arterial blood gas (ABG) is 7.32/34/98 on FiO2 of 0.5. She is noted to have hepatosplenomegaly, but no rash, asymmetric lower extremity edema, or lymphadenopathy. Laboratory data reveal:
Chest x-ray reveals resolving bilateral patchy opacities and mild pulmonary edema. Point of care cardiac ultrasound shows hyperdynamic biventricular function. Culture data are negative to date.
Which of the following tests would BEST to confirm her diagnosis:
Correct Answer: A
Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory condition characterized by excessive immune activation of macrophages and T cells. This results in elevated levels of inflammatory cytokines including interferon gamma and tumor necrosis factor alpha. Etiologies include genetic mutations, infection, inflammatory disease, and malignancy. Genetic mutations are more common in children. Increasingly, there is evidence that HLH induced by infection is underdiagnosed in the ICU.
HLH may be diagnosed with five of the following eight criteria:
Alternatively, diagnosis may be made with a positive genetic testing. HLH remains a difficult diagnosis to make in the critically ill, as many of the symptoms are nonspecific and exist in a variety of inflammatory and infectious conditions including sepsis. HLH should be a part of the differential in patients with persistent fever, hepatosplenomegaly, elevated ferritin, cytopenia (without alternative explanation), and failure to improve with appropriate antimicrobials.
In this case, the patient has failed to improve on broad-spectrum antimicrobials. She has pancytopenia, hepatosplenomegaly, and persistent fever, making HLH a possible diagnosis. The next best test to confirm a diagnosis of HLH is to measure ferritin, triglycerides, fibrinogen, and soluble IL-2 receptor levels. Bone marrow biopsy may also be considered but is more invasive.
Platelet factor 4 is a diagnostic test for HIT type II, caused by antibodymediated destruction of platelets. The confirmatory test is a serotonin release assay. Peripheral smear and flow cytometry are not required to diagnose HLH. ANCA is a laboratory test used for the assessment of vasculitis.
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A 68-year-old diabetic man, who had open sigmoidectomy 10 days ago for diverticulitis, is brought to emergency department (ED) after his son found him altered at home. Initial vitals are notable for:
His blood glucose is normal. Blood cultures, chest x-ray, urinalysis, and urine culture are obtained. He is given vancomycin, cefepime, metronidazole, and 2 L of lactated Ringer’s and is subsequently intubated for airway protection. CT scans of the head, chest, abdomen, and pelvis, obtained before the ICU admission, are unremarkable.
On ICU arrival, detailed physical examination reveals diffuse erythematous blanching rash and hyperemic mucus membranes of the mouth and conjunctiva. His abdominal incision is slightly erythematous but without frank purulence
Subsequent management should include which of the following?
Correct Answer: B
Toxic shock syndrome (TSS) is a life-threatening condition because of Staphylococcus aureus or group A Streptococcus toxin. Patients with surgical and postpartum wounds and, classically, menstruating women are at increased risk. Diagnostic criteria for TSS include fever greater than 38°C, multisystem organ dysfunction including vomiting or diarrhea (often watery), muscular symptoms (myalgias/creatine phosphokinase levels >2× upper limit of normal), mucus membrane involvement, renal dysfunction or pyuria in the absence of urinary tract infection, hepatic dysfunction (elevated bilirubin and aminotransferases), thrombocytopenia, and altered mental status without focal neurologic findings.
The pathophysiology of TSS involves super antigens that cause overwhelming T-cell activation leading to a state of cytokine storm with high levels of IL-1, IL-2, and TNF-alpha and beta, as well as interferon gamma. Super antigens involved in the pathophysiology of TSS include TSST-1 and staphylococcal enterotoxins (A-D).
The best empiric antibiotic management while awaiting culture data is IV clindamycin (to halt toxin synthesis) and vancomycin (methicillinresistant Staphylococcus aureus coverage). Piperacillin-tazobactam is not an optimal antibiotic regimen as it does not have appropriate methicillinresistant Staphylococcus aureus coverage and will not decrease toxin production.
There is currently clinical equipoise regarding the use of intravenous immunoglobulin (IVIg), although observational comparative studies have demonstrated that IVIg is associated with significantly lower mortality at 28 days. The mechanism is thought to include neutralization of the super antigens. This treatment is not ubiquitously used at all institutions.
A 68-year-old man with bronchiectasis and severe pneumonia is mechanically ventilated in the ICU. He is treated with empiric meropenem and vancomycin based on the culture data obtained during prior admission, and his blood pressure is supported with norepinephrine. On ICU day 3, his sputum culture reveals ceftriaxone-susceptible Streptococcus pneumoniae. Thirty minutes after the dose of ceftriaxone, he is noted to have worsening hypotension and requires increasing doses of norepinephrine. As ICU physician prepares to perform cardiac ultrasound, he notices urticaria on his chest.
Which of the following laboratory tests would clarify the diagnosis?
Anaphylactic shock is a life-threatening condition that may be difficult to recognize in sedated, intubated patients. Clinical manifestations include increased peak airway pressures, urticarial rash, hypotension, or cardiac arrhythmias. The patient in the vignette has bronchiectasis and history of previous admissions for pneumonia, for which he likely received cephalosporin antibiotics in the past.
Anaphylaxis may either be IgE mediated or non-IgE mediated. In IgEmediated anaphylaxis, mast cell degranulation, and histamine and protease release (ie tryptase) lead to the clinical manifestations. Non-IgE– mediated anaphylaxis occurs via neutrophil, eosinophil, and complement activation. Common triggers of anaphylaxis include antibiotics, nonsteroidal anti-inflammatory medications, certain anesthetic agents, food and insect venom.
Biomarkers, if positive, are useful in diagnosing anaphylaxis. Tryptase has a plasma half-life of approximately 2 hours. For comparison, a baseline tryptase level should be measured 24 hours after resolution of anaphylaxis to ensure accurate interpretation. Owing to the kinetics of tryptase release, it is the most clinically useful serum marker of anaphylaxis. While histamine is released by mast cells during anaphylactic reactions, peak serum levels occur within 5 to 10 minutes and return to baseline within 1 hour, making it a suboptimal clinical biomarker. ACE level is not a marker of anaphylaxis. Nonspecific changes during anaphylaxis may be seen on CBCs including leukocytosis, neutrophil predominance, and possibly increased eosinophilia. However, this pattern may be seen in a variety of conditions and would not confirm the diagnosis. Further, in a patient with suspected infection, leukocytosis and neutrophil predominance would be expected.
A 23-year-old female with refractory acute lymphoblastic leukemia now 28 days postallogeneic hematopoietic stem cell transplant (HSCT) is transferred to the ICU for respiratory distress. On arrival, vital signs are:
She is saturating 88% on 10 L O2 via nonrebreather. Pulmonary examination is notable for diffuse rales. She does not have a rash, and her sclerae are mildly icteric. She is subsequently intubated and started on norepinephrine infusion for hypotension with improvement in hemodynamics. Broad-spectrum antibiotics are administered for concern of pneumonia. Chest x-ray shows diffuse bilateral patchy opacities.
The next BEST diagnostic step is:
Pulmonary complications following HSCT are common. The differential for pulmonary complications is very broad and includes infection, diffuse alveolar hemorrhage, edema, engraftment syndrome, idiopathic pneumonia syndrome, and graft versus host disease.
Engraftment is defined as recovery of cell counts with absolute neutrophil count > 500/mm3 . Engraftment occurs within 2 to 4 weeks of transplantation. Engraftment syndrome is characterized by fever, rash, and evidence of capillary leak including pulmonary edema and weight gain. Other manifestations include dyspnea and noninfectious pulmonary infiltrates on imaging. Hepatic, renal dysfunction, or transient encephalopathy may be present. All symptoms occur within 4 days of reaching an absolute neutrophil count of 500/mm3 . Therefore, neutropenia is temporally proximal to symptoms, and empiric antibiotics should be initiated while awaiting culture data. If there is no improvement on appropriate antibiotics after 48 to 72 hours, a diagnosis of engraftment syndrome should be considered. Respiratory failure is the largest contributor to mortality related to engraftment syndrome. Treatment includes steroids (such as methylprednisolone) administered until symptoms resolve (typically 2-3 days), followed by oral prednisone.
Patients are immunocompromised following HSCT and therefore the differential for pulmonary infections includes bacterial, fungal, and viral pathogens. Infections most commonly occur before engraftment during periods of neutropenia but may occur at any time. Viral infections in the early posttransplant period include CMV pneumonia, RSV, influenza A, B, HSV, or varicella-zoster virus (VZV). Fungal infections include aspergillus, pneumocystis and less commonly zygomycetes, rhizopus, and mucor. Treatment is initially broad-spectrum antimicrobials, which can be narrowed based on culture data.
The patient in the above vignette is 28 days post transplant. The differential is extremely broad. Therefore, workup should include bronchoalveolar lavage (BAL) to rule out diffuse alveolar hemorrhage, infectious etiologies, and CT of the chest to evaluate the presence of infection, pulmonary edema, and infiltrates. Steroids are the treatment for several of the conditions on the differential including engraftment syndrome, graft versus host disease (GVHD), and diffuse alveolar hemorrhage. However, empiric steroids without exoneration of infection would not be a correct treatment at this time. HSV and CMV PCR may diagnose viremia, however, would not exclude alternative diagnoses such as diffuse alveolar hemorrhage and GVHD and therefore are not the next best correct test. 1-3-beta-d-glucan is a fungal marker and galactomannan is elevated with invasive aspergillosis. If positive, the test suggests fungal infection. However, it would not rule out nonfungal causes of the patient’s respiratory failure.
A 65-year-old male who is postoperative day (POD) 3 from right hemicolectomy for cancer is admitted to the ICU for hypoxemia. His HR is 120/min, oxygen saturation is 88% on 15 L oxygen, and he requires intubation. Chest x-ray shows right middle and lower lobe opacities consistent with pneumonia. Mean arterial pressure (MAP) is 65 mm Hg on 5 µg/min of norepinephrine. He is started on broadspectrum antibiotics including vancomycin, cefepime, and metronidazole. Laboratory results are notable for:
Physical examination reveals digital necrosis of several fingers and toes.
What is the most likely cause of his coagulopathy?
Correct Answer: C
This patient has septic shock because of hospital-acquired pneumonia and evidence of coagulopathy consistent with DIC. DIC is characterized by hypercoagulability and hyperfibrinolysis resulting in phenotypes ranging from massive bleeding to excessive microvascular thrombosis resulting in multisystem organ failure. Laboratory abnormalities in DIC include prolongation of aPTT, PT/INR, hypofibrinogenemia, decreased platelets, and elevated fibrinogen split products including d-dimer. The treatment of DIC involves treating the underlying cause. Transfusion thresholds typically include platelets ≤50/ µL in bleeding patients and ≤10 to 20/ µL in those whom are not. Fresh frozen plasma may be transfused to correct prolonged aPTT or prothrombin time (PT) and to replenish clotting factors being consumed. In patients who develop hypofibrinogenemia, administration of cryoprecipitate corrects this abnormality. In patients with clotting predominant DIC, heparin or low molecular weight heparin are utilized to prevent further thrombosis.
Sepsis itself may cause thrombocytopenia, which would however not explain global coagulopathy seen in this patient. Although thrombocytopenia and schistocytes are also present in TTP, this syndrome is characterized by normal coagulation times. HIT is not associated with abnormal coagulation times.
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