A 50-year-old female underwent allogeneic stem cell transplantation for acute myeloid leukemia 10 days ago. She is brought to the ICU with fevers and hypotension. She is neutropenic. She noticed a red rash on her trunk and extremities yesterday. On examination, she appears ill and is febrile (38°C). Her blood pressure is 84/60 mm Hg, heart rate 120 beats per minute, and respiratory rate 36 breaths per minute. Her central venous catheter site is clean and nontender. Physical examination demonstrates grade 3 mucositis of her buccal mucosa, a diffuse erythematous, blanchable rash, and bilateral crackles on auscultation of her posterior lung fields. Her chest x-ray demonstrated bilateral diffuse infiltrates. A bedside echocardiogram showed normal valves with preserved left ventricular function. Her blood cultures grow gram positive cocci in pairs and chains in both sets of aerobic and anaerobic bottles collected on transfer.
What is the MOST LIKELY diagnosis?
Correct Answer: E
The diffuse erythematous skin rash, fever, and hypotension in a neutropenic patient with mucositis are consistent with septic shock due to viridans group streptocococci (VGSS).
Viridans streptococci are normal inhabitants of oral cavity. They are classified into six major groups. Streptococcus mitis is the group of organisms most commonly associated with septic shock. VGSS is a relatively new entity first described in 1990s. The incidence of shock and/or acute respiratory distress syndrome varies from 7% to 39%. Risk factors for bacteremia include profound neutropenia (<100 cells/µL), oral mucositis, and prophylactic fluoroquinolone use. Patients receiving ceftazidime as empiric therapy for febrile neutropenia are also at increased risk. Reduced susceptibility to penicillins and newer beta-lactam agents raise concerns in the management of severe infections due to VGSS. Empiric therapy with vancomycin is suggested until final susceptibilities of the organism are available. Mortality ranges from 6% to 30%.
The identification of gram positive cocci in pairs and chains makes staphylococcal infection unlikely. The clinical scenario is not suggestive of infective endocarditis (IE). Causes for hypotension in IE are septic shock, more common with Staphylococcus aureus IE and cardiac failure due to severe valvular regurgitation. Enterococcal IE is rarely implicated in septic shock syndromes, more commonly observed with staphylococcal infection.
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A 39-year-old male who underwent a haploidentical allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia 2 years ago is admitted to the ICU with acute hypoxic respiratory failure requiring supplemental oxygen through a highflow nasal cannula. His HSCT was complicated by graft-versus-host disease (GVHD) of the skin and gastrointestinal tract 6 weeks ago for which he was treated with pulse dose steroids. He was recovering from an upper respiratory tract infection caused by rhinovirus (nasopharyngeal swab PCR positive) 3 weeks ago when he started to experience shortness of breath that progressively worsened. His WBC count was 4.5 cells/µL with 80% neutrophils on admission. His creatinine was elevated at 2.1 mg/dL (baseline: 1 mg/dL). A CT scan of the chest without contrast revealed multifocal nodular opacities with right-sided predominance. Blood cultures, urine histoplasma antigen, serum cryptococcal antigen, and serum Aspergillus galactomannan were negative. His serum β-1,3-d-glucan assay was positive. The patient’s sputum culture grew normal respiratory flora. He was started on intravenous vancomycin and piperacillintazobactam, but his respiratory status continued to decline eventually requiring intubation 2 days into his admission. Bronchoscopy was performed with bronchoalveolar lavage (BAL). Initial stains on the BAL fluid showed nonpigmented, septate hyphae branching at right angles.
What is the NEXT step in the antimicrobial management of this patient?
Correct Answer: C
The presence of a positive serum β-1,3-d-glucan assay and BAL fluid nonpigmented, septate hyphae branching at right angles in a stem cell transplant recipient with recently increased immunosuppression for treatment of GVHD suggests invasive pulmonary aspergillosis. Filamentous fungi are divided into septate and aseptate forms as shown in the following figure. Organisms which characteristically present with septate hyphae include Aspergillus and Fusarium, but Fusarium grows easily in blood cultures, making it less likely in this case.
Voriconazole is the first-line treatment for invasive pulmonary aspergillosis. Careful monitoring of serum creatinine is needed in patients receiving intravenous voriconazole due to the potential accumulation of cyclodextrin which is the carrier for the intravenous formulation. The lipidbased formulation of amphotericin B and isavuconazole serve as alternative for patients who cannot tolerate voriconazole due to side effects or drug-drug interactions.
A 26-year-old female with a history of sickle cell disease complicated by multiple sickle cell crises in the past year is admitted to the ICU with acute hypoxic respiratory failure and shock. On arrival to the ICU:
She is intubated and mechanically ventilated. Initial laboratory evaluation demonstrates a neutrophilic- predominant leukocytosis to 14 000 cells/µL. Her chest x-ray on admission shows a left lower lung infiltrate with an associated pleural effusion. Blood cultures are in process.
What would be the NEXT BEST STEP to confirm this patient’s diagnosis?
In a patient with history of sickle cell disease and multiple sickle cell crises in the past, there is increased suspicion for repeated infarction to the spleen and resultant functional asplenia. Asplenic patients are at increased risk for a fulminant sepsis syndrome usually due to encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenza, and Neisseria meningitides due to their reduced antibody formation to polysaccharide antigens. (table below):
The risk of sepsis is dependent on the age of the patient and cause of asplenia. In patients with hemoglobinopathies, the risk of sepsis is greater in children than in adults, but in patients with splenectomy, the risk of sepsis increases after the age of 50. Patients with sickle cell anemia or thalassemia major are three to four times more likely to experience sepsis compared with patients with splenectomy secondary to trauma.
Other causes for asplenia/hyposplenism include postsurgical splenectomy, splenic artery thrombosis, graft-versus-host disease, inflammatory bowel disease, SLE, and HIV/AIDS. Acutely ill patients should undergo appropriate diagnostic evaluation and receive empiric broad-spectrum antibiotic therapy. The single most valuable diagnostic test in evaluating a patient with suspected postsplenectomy sepsis is blood culture, as the bacterial burden in the blood may be high. In this particular patient, given her increased risk for S. pneumonia–related sepsis, obtaining an urine antigen may be helpful to confirm diagnosis.
Recommended empiric antibiotic therapy includes vancomycin and either a third-generation cephalosporin such as ceftriaxone or an extendedspectrum fluoroquinolone such as levofloxacin or ciprofloxacin. Blood cultures and antibiotic susceptibility results will guide subsequent antibiotic selection. Administration of antibiotics should not be delayed pending diagnostic studies, including lumbar puncture if indicated.
A 45-year-old female who underwent bilateral lung transplantation 6 days ago is brought to the ICU intubated following a seizure episode. Her transplantation was uneventful and she was transferred to a regular nursing floor on postoperative day 4. She was intubated at bedside for airway protection and brought to the ICU. On examination, the patient is sedated and her pupils were mildly dilated but equally reactive to light. Her blood pressure was 110/90 mm Hg and heart rate 120 beats per minute. Mild purulence is noted from the lower part of sternotomy site with no obvious instability or bony crepitations. The output from her chest drains was nonpurulent. An arterial blood gas shows an elevated lactate of 2.5 mmol/L, partial pressure of oxygen of 92 mm Hg, and partial pressure of carbon dioxide of 38 mm Hg. Her laboratory results demonstrate:
Blood cultures are collected. Wound cultures sent from the regular nursing floor prior to transfer show numerous neutrophils but a negative gram stain. A CT scan of the brain did not show any acute abnormalities. Debridement of sternal wound is done and the patient is started on empiric vancomycin and piperacillin-tazobactam.
What is the NEXT BEST step in the management of this patient?
This patient with seizures in the postoperative lung transplant period most likely has hyperammonemia syndrome due to Mycoplasma hominis sternal wound infection. Hyperammonemia is a rare but fatal cause of altered mental status in lung transplant recipients, with an incidence of 4.1%. Among infectious causes for this syndrome, Mycoplasma hominis and Ureaplasma are the two most important culprit organisms and involve the release of ammonia as a by-product of urea metabolism.
M. hominis is a fastidious bacteria. Gram stains cannot detect the organism due to the absence of a peptidoglycan cell wall. It is a common colonizer of the urogenital tract in females and usually causes genitourinary infections. In 10% of adults, M. hominis colonizes the upper respiratory tract and can cause life-threatening infections after thoracic organ transplantation and other cardiothoracic surgeries, including mediastinitis, pleuro-pericarditis, and sternal osteomyelitis.
M. hominis is diagnosed by culture and PCR testing. The organism is usually susceptible to clindamycin or doxycycline. The organism is usually resistant to fluoroquinolones, macrolides, and aminoglycosides.
A 65-year-old former Vietnam War veteran male was admitted to the intensive care unit with shock. He had underwent orthotopic liver transplantation 3 months ago for cirrhosis due to alcohol abuse and hepatitis C infection. His posttransplant course had been complicated by graft-versus-host disease treated with pulse dose methylprednisolone for 3 days followed by prednisone 60 mg daily, which he was currently on. He presented to the emergency room with complaints of headache and wheezing for the last 2 days and was also found to be somnolescent. On the first day of admission, he was noted to have intermittent bouts of cough with two episodes of small volume hemoptysis. Chest x-ray showed bilateral patchy nodular opacities for which he was started on vancomycin and piperacillin/tazobactam. However, on the second day of admission, his condition acutely worsened with tachycardia, hypoxemia, and hypotension requiring vasopressor support. Lactate was elevated raising suspicion of sepsis, and workup for an infectious source was initiated. Urinalysis was unremarkable, stool Clostridioides difficile PCR was negative, and CMV PCR was undetectable in blood. CT scan of the head was unremarkable. Two sets of blood cultures were sent. Gram stain of cerebrospinal fluid (CSF) showed gram-negative rods identified later the same day as Escherichia coli by PCR, and consequently piperacillin/tazobactam was changed to cefepime. Chest imaging the next day showed marked worsening of opacities on the left upper lobe and right lower lobe, and he was intubated for worsening hypoxia. The tracheal aspirate was sent for culture; however, you received a call from the microbiology lab the same day informing you of an unexpected finding on the gram stain of tracheal aspirate. A representative image below:
Which of the following describes the best treatment plan for this patient?
This patient’s presentation of sepsis with gram-negative meningitis likely from gram-negative bacteremia, rapidly evolving pulmonary infiltrates, and larvae seen in sputum taken together is typical of Strongyloides hyperinfection.
Strongyloides infection is usually asymptomatic, and when present, the symptoms are typically mild and limited to cutaneous larva migrans rash at the site of penetration of the skin by filariform larvae, intermittent cough or dyspnea during larval migration through the airways, and diarrhea with or without abdominal discomfort. Hyperinfection is a rare syndrome of strongyloidiasis characterized by uncontrolled overproliferation of larvae leading to an exaggeration of the usual symptoms and sometimes causing a dramatic systemic inflammatory response to dissemination and migration of larvae throughout the body. Typical manifestations include fever, wheezing or asthma-like symptoms, hemoptysis, ileus, gastrointestinal bleeding, pneumonitis with or without pneumonia and alveolar hemorrhage, transient bacteremia secondary to translocation along by the larvae penetrating the intestinal mucosa with or without secondary organ seeding, and meningitis. Together these symptoms lead to multiorgan failure with a high rate of mortality.
Hyperinfection has classically been described with corticosteroid use; however, it has been reported with various other immunosuppressive medications and conditions including human immunodeficiency virus (HIV), solid organ, and hematopoietic stem cell transplantation. The underlying mechanism is deemed to be an impairment in cell-mediated immunity. Human T-cell leukemia/lymphoma virus-1 infection, by itself, predisposes to strongyloidiasis and also to hyperinfection without any other immune suppression. Solid-organ transplant recipients who have not been exposed to Strongyloides can potentially acquire it from an infected donor’s organ; high-risk regions routinely screen for Strongyloides in the donor with positive serological screening prompting preemptive treatment of the organ recipients. Eosinophilia, the hallmark of invasive parasitic infections including strongyloidiasis may be absent in hyperinfection syndrome especially if steroids are being used. Of note, even short courses of steroids up to a week and at doses as low as 20 mg per day have been reported to have precipitated hyperinfection within a few days to weeks.
Treatment of strongyloidiasis hyperinfection is a three-pronged approach aimed at (1) targeting the underlying worms while (2) decreasing immunosuppression to allow the body to respond to the infection adequately and at the same time (3) covering for secondary complications like bacteremia with or without seeding. Ivermectin remains the antiparasitic of choice. The oral route is preferred, but if oral absorption is a concern, subcutaneous or intravenous formulations of ivermectin can be used off-label. Albendazole can be added for severe cases although the benefit of this is unclear. Although the presence of larvae or eggs in the stool is not the best diagnostic modality in the setting of chronic infection, in hyperinfection the parasitic is high enough that stool parasites should be ideally monitored for clearance and antiparasitic therapy should be continued for at least 2 weeks after that to cover for autoinfection. All attempts should be made to hold or decrease any immunosuppressive therapies that the patient is on. Antimicrobials targeting gram-negative and gram-positive gut commensals should be used to treat bacteremia. Prophylactic antimicrobials are appropriate even in the absence of microbiological evidence of bacterial infection in the acute setting given the high likelihood of the same.
This patient likely acquired Strongyloides during his service in Vietnam and his latent infection became clinically active in the setting of high-dose steroids for graft-versus-host disease of his recently transplanted liver, although it is possible that the infection had become active around the time of his transplant, and the manifestations became more severe with steroid use.
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