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Introduction Febrile neutropenia is a clinical emergency that can develop as a result of multiple mechanisms. The evolution of neutropenia is highly dependent on that of the underlying disease, and identification of comorbidities is essential. In cases of Gram-negative bacteremia, the mortality rate can reach 18%. Case report We report the case of a patient with myelodysplastic syndrome and neutropenia among multiple comorbidities, hospitalized for fever, chills and altered clinical state two weeks after having been discharged from the hospital following the resolution of sepsis with P. aeruginosa. The clinical exam revealed active intestinal bleeding and discrete wet rales in the middle one-third of the right pulmonary lung field. An initial diagnosis was neutropenic fever, and empirical intravenous treatment with meropenem, vancomycin and caspofungin was started. A comprehensive laboratory evaluation revealed liver and kidney impairment of recent onset, blood cultures came back positive for P. aeruginosa, and the diagnosis of recurrent sepsis with P. aeruginosa was established. Antimicrobial treatment was de-escalated from meropenem to piperacillin-tazobactam, levofloxacin was added, vancomycin was stopped, and caspofungin was replaced with fluconazole, with favorable evolution, remission of fever within three days, marked reduction of the inflammatory syndrome, and remission of organ impairment. Treatment was continued for 10 days before the patient was discharged with the recommendation to continue prophylaxis with levofloxacin and fluconazole for the duration of severe neutropenia and to return for periodic evaluation in our clinic. Conclusions The recurrent sepsis episodes in this patient reflect primarily the neutropenic status, but comorbidities could also contribute to a certain degree of immunodeficiency. The long-term management of the infectious risk is a complex issue, including antibiotic and antifungal prophylaxis, due to the anticipated persistent neutropenia.
The evolution of the underlying disease is critical as it also dictates the evolution of neutropenia, and thus, the patient’s susceptibility to bacterial or fungal infections. We present the case of a 65-year-old female with two consecutive episodes of sepsis occurring on a clinical background of immunosuppressive disorder, illustrating the complexity of factors that might lead to systemic infections.
Case report
A 65-year-old female patient with myelodysplastic syndrome was hospitalized in our infectious diseases clinic for fever (38.5°C), chills and altered clinical state, which had all started 4 days previously. Clinical examination at hospital admission revealed jaundice, bilateral thrombocytopenic purpura of the thighs and calves, two indurated oval purple lesions (0.5 cm in diameter) suggestive for ecthyma gangrenosum, on the anterointernal side of the left calf, abdominal spider angioma and spontaneous bleeding (epistaxis, melena, bleeding gums and rectorrhagia. The chest auscultation showed discrete wet rales in the middle one-third of the right pulmonary lung field, and mild pain on palpation of an abdomen presenting moderate ascites.
The patient had a complex medical history: right breast cancer (diagnosed 20 years previously, for which the patient had undergone surgical removal, chemotherapy and hormonal therapy), atrophic gastritis and B12 vitamin deficiency, hepatic cirrhosis due to chronic co-infection with hepatitis B and delta viruses (HBV and HDV) diagnosed 30 years previously, and a myelodysplastic syndrome with excess blasts type 1 (RAEB 1) diagnosed one year previously, for which the patient was undergoing treatment with azacitidine (currently at the second course of treatment).
Notably, the patient had been previously hospitalized in our clinic for sepsis with Pseudomonas aeruginosa, and Clostridioides difficile enterocolitis, having been treated with intravenous meropenem, oral vancomycin, and intravenous anidulafungin.
Laboratory examinations (Table 1) during the current hospital admission revealed severe pancytopenia, marked inflammatory syndrome, predominance of the alpha 1 fraction in protein electrophoresis, nitrogen retention syndrome (urea 55 mg/dL, creatinine clearance 31 mL/min), incomplete hepatic cholestasis, minimal hepatic cytolysis (aspartate aminotransferase 39 U/L, alanine aminotransferase 57 U/L), and hypoalbuminemia (3.19 g/dL). The ECG was normal, and a cardiac ultrasound identified a mild hypertrophy of the left ventricle, grade 2 mitral regurgitation, slight dilation of the left atrium, and excluded the presence of pericarditis, or vegetations suggestive for infectious endocarditis. Urinary exams returned normal biochemistry results, no leukocytes or red blood cells, and negative cultures. Ascites fluid exams also returned Gram smears negative for bacteria, and negative cultures. Blood cultures were also collected upon hospital admission.
Blood cultures drawn at admission showed susceptibility of P. aeruginosa to all tested antimicrobials (piperacillin-tazobactam, anti-pseudomonal cephalosporins and anti-pseudomonal carbapenems, aminoglycosides and fluoroquinolones), except for aztreonam, to which the isolate displayed intermediate susceptibility. Based on the antimicrobial susceptibility pattern, antimicrobial treatment was de-escalated from meropenem to piperacillin-tazobactam 4/0.5 g i.v. q6h, levofloxacin 750 mg p.o q24h was added, vancomycin was stopped, and caspofungin was replaced with fluconazole 200 mg i.v. q12h, since a fungal infection was ruled out, but the patient continued to present severe neutropenia. Apart from antimicrobial therapy, the patient also received daily transfusions of packed red blood cells, as well as pathogenic and symptomatic treatment.
Under antimicrobial therapy, the patient displayed favorable evolution with remission of fever within three days, marked reduction of the inflammatory syndrome, as well as remission of liver and kidney impairment. Treatment was continued for the whole duration of hospital admission (a total of 10 days), and then the patient was discharged with the recommendation to continue prophylaxis with levofloxacin 500 mg p.o. q24h and fluconazole 200 mg p.o. q24h for the duration of severe neutropenia and to return for periodic evaluation in our clinic.
We have presented the case of a neutropenic patient who presented two consecutive hospital admissions for sepsis with P. aeruginosa, in the absence of antimicrobial prophylaxis following the first infectious episode. Fluoroquinolone prophylaxis in patients with prolonged neutropenia is currently under debate, after having been recommended as standard of care since 2005.3 However, a recent meta-analysis has shown that while fluoroquinolone prophylaxis may indeed reduce the incidence of bloodstream infections, it does not seem to impact overall mortality, and it may lead to increased rates of either colonization or infection with fluoroquinolone-resistant or multidrug-resistant bacterial strains.4 In our patient with myelodysplastic syndrome, neutropenia was expected to continue on the long term, and therefore following the first episode of sepsis, a risk-benefit analysis of fluoroquinolone prophylaxis suggested that treatment could be stopped. However, the recurrence of Pseudomonas infection in the absence of antimicrobial prophylaxis warranted the recommendation to institute fluoroquinolone prophylaxis following the second infectious episode; prophylaxis was well tolerated and ensured the sustained clinical remission of infection.
This febrile neutropenic patient had several particularities that could have led to an immunodeficient status, that we will briefly summarize here.
The central mechanism of the immunodeficiency was the hematological disease. The patient had been diagnosed one year before with refractory anemia with excess blasts, a subtype of myelodysplastic syndrome, manifested in her case with prolonged pancytopenia. The myelodysplastic syndrome affects stem cells and usually leads to anemia, or, less frequently, to bi- or pan-cytopenia, as in our case. Survival of patients with RAEB 1 myelodysplastic syndrome is poor (14-17 months), and even with hematopoietic stem cell transplantation it increases only to 55.6-62.2 months, depending on the initial percentage of bone marrow blast cells.5 Neutropenia is the main predisposing factor for infection, but neutrophil dysfunctions (morphological anomalies, reduction in phagocytosis and production of oxygen radicals, myeloperoxidase, lactoferrin and other components of the neutrophil granules), lymphocytic defects (modified B-cell and antibody production, a decrease in T-helper lymphocytes, impairment of regulatory T-cells, damage of NK cells) and iron overload caused by repeated red blood cell transfusions may also be contributing factors. Iron overload is, on the one hand, a favorable milieu for pathogen growth and on the other hand, it impairs the natural defense mechanism against infections by inhibiting IFN-gamma, TNF-, IL-12 and nitric oxide production, and by impairing macrophage, neutrophil and T-cell functions).6
Infections in patients with myelodysplastic syndromes are caused by bacteria and rarely by viruses,6 while fungi may also represent important etiological agents, particularly in patients with severe neutropenia. In our patient, blood cultures identified P. aeruginosa as the etiologic agent of pulmonary-derived sepsis. P. aeruginosa is an opportunistic Gram-negative bacterium with numerous virulence factors and mechanisms of resistance to antibiotics7, that is frequently involved in nosocomial infections, but can also be an agent of community-acquired infections, particularly in patients with impaired immune status, since it is an ubiquitous germ. In the case we have presented, the bacterial isolate was pan-susceptible, suggesting it had probably been acquired in the community.
In patients with sepsis, it is essential to ensure that the primary source of infection is also controlled. The most frequent primary sources of infection are urinary infections, pneumonia, catheterization and infections of the pancreaticobiliary tract.8 In the case we have presented, the primary infection most probably originated in the lower respiratory tract, and we also identified a secondary cutaneous determination, ecthyma gangrenosum. Another source of the infection that could not be ruled out was the intestinal tract. In oncology hematology units, 11.7-37% of patients have been shown to be intestinal carriers of P. aeruginosa.9The translocation is mediated by different virulence factors such as adhesins, proteases and elastases secreted by the bacteria.10 Gut bleeding could also have facilitated, in this patient, the translocation of P. aeruginosa. Thrombocytopenia impairs leukocyte recruitment and activation and limits the defense reaction against microorganisms at the natural barriers, such as the gut epithelia.11In sepsis, thrombocytopenia increases the risk of mortality and the progression to the stage of multi-organ failure.12-14
A second plausible immunodeficiency mechanism in the case we have reported here, was inevitably related to the azacitidine treatment of the myelodysplastic syndrome. Infections are generally reported to occur after the second course of treatment, since azacitidine can exacerbate cytopenia.15In a controlled trial consisting of 191 subjects who were randomized to treatment with azacitidine or to observation, febrile neutropenia was one of the most frequent severe adverse events.16 Adverse events following treatment with azacitidine have been reported to attenuate with every course of treatment and they are not cumulative.15 Taking into account that our patient was only at the second cycle of treatment, we may consider that azacitidine administration also contributed to her high susceptibility to infections.
A third risk factor for severe infections was the presence of hepatic cirrhosis, that had developed over the course of thirty years of co-infection with HBV and HDV. Hepatic cirrhosis may associate a certain degree of immunodeficiency, systemic inflammation, increased susceptibility to bacterial infections, altered response to vaccination and increased gut bacterial translocation.17 A disrupted architectural and cellular organization of the liver leads to a less efficient reticuloendothelial system, deficiency in the clearance of endotoxins and bacteria, and an imbalanced protein synthesis. In our patient, the high C-reactive protein (CRP) was not mirrored by a high fibrinogen value, despite the presence of active systemic inflammation (Table 1). This pattern of high CRP and normal fibrinogen has been previously described in field literature when characterizing patients with liver cirrhosis.18 In our patient, the relative fibrinogen decrease could also be the consequence of the coagulation activation-induced consumption. The erythrocyte sedimentation rate value was also significantly elevated, as a result of the acute phase reactants being present in serum. The majority of these acute phase proteins migrate inside the alpha zone. In the specific case of our patient, the preexistent cirrhosis would probably have set a high value of the alpha 2 macroglobulin, the major component of the alpha electrophoretic band. In sepsis however, alpha 2 macroglobulintends to diminish, and this decrease has even been considered a specific biomarker to differentiate between bacterial sepsis and systemic inflammatory response syndrome. The cause of this decrease is not well known. Most probably it is related to a higher utilisation.19
Circulating immune cells are also compromised; both their number and function are damaged (sequestration in the spleen, altered phagocytosis, impairment of intracellular signaling, chemotaxis dysfunctions).20Cirrhosis in our patient could also have played a role in the pathogenesis of recurrent sepsis, the risk of P. aeruginosa sepsis having been described by Bang et al. to be 3-fold higher in patients with liver cirrhosis due to chronic HBV infection who had also been exposed to immunosuppressive drugs.21
Considering all the elements described above, we conclude that the sepsis episodes in our patient reflect a complex immunodeficiency status following the cumulative effects of multiple mechanisms: medullar dysfunction, immunosuppressive treatment, and cirrhosis-associated immune deficit.
We have described a case of recurrent sepsis with a community-acquired strain of Pseudomonas aeruginosa in a patient with myelodysplastic syndrome who also presented the co-existence of multiple mechanisms of immunodeficiency. The long-term management of the patient was difficult, due to the anticipated persistent neutropenia, particularly since prophylactic antimicrobial therapy has its limitations and associates a risk of selection of resistant strains.
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