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Pneumocystis Jiroveci Pneumonia Following Kidney Transplantation: a Retrospective Analysis of 22 Cases

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Pneumocystis Jiroveci Pneumonia Following Kidney Transplantation: a Retrospective Analysis of 22 Cases Int J Clin Exp Med 2017;10(1):1234-1242 www.ijcem.com /ISSN:1940-5901/IJCEM0025412 Original Article Comparison of caspofungin and trimethoprim-sulfamethoxazole combination therapy with standard monotherapy in patients with Pneumocystis jiroveci pneumonia following kidney transplantation: a retrospective analysis of 22 cases Bo Yu1, Yu Yang1, Linyang Ye1, Xiaowei Xie2, Jiaxiang Guo1 Departments of 1Urology, 2Pulmonology, The First Affiliated Hospital of PLA’s General Hospital, Fu Cheng Road 51#, Haidian District, Beijing 100048, China Received February 1, 2016; Accepted April 27, 2016; Epub January 15, 2017; Published January 30, 2017 Abstract: Pneumocystis jiroveci pneumonia (PCP) is one of the most common and fatal opportunistic infections of renal transplant recipients. The objective of this retrospective study was to compare the therapeutic effect and safety of caspofungin and trimethoprim-sulfamethoxazole (TMP-SMZ) combination therapy with standard TMP- SMZ monotherapy in 22 patients with severe PCP following kidney transplantation. The presence of P. jiroveci was determined by direct fluorescence staining, PCR analysis, detection of beta-1, 3-glucan and serum lactate dehy- drogenase levels. Thirteen patients received combination therapy, and nine patients received standard TMP-SMZ monotherapy for PCP. There were no significant differences in the baseline demographics and clinical characteris- tics were detected. Patients in the combination therapy group experienced better overall outcomes characterized by reduced duration of increased body temperature (P < 0.001), respiratory intensive care unit stay (P < 0.001), less requirement for mechanical ventilation (P = 0.005) and shorter high dosage TMP-SMZ treatment course (P < 0.01). 44.4% of patients receiving standard TMP-SMZ progressed to acute respiratory distress syndrome (ARDS), none of the patients in the combination therapy group experienced ARDS (P = 0.017). In addition, patients in the combination treatment group had greater PaO2/FiO2 (P = 0.007), and experienced less neutropenia. Two patients in the TMP-SMZ monotherapy group died, while no deaths were observed in patients receiving combination therapy. In conclusions, PCP patients receiving caspofungin and TMP-SMZ co-treatment may experience better clinical out- comes with fewer side effects. Large-scale, prospective studies are needed to confirm that the improved clinical outcomes were due to the combination therapy. Keywords: Kidney transplantation, immunosuppression, opportunistic infection, respiratory failure, beta-1, 3-glu- can Introduction se reduction [6, 7]. Given the high mortality rates associated with PCP, new treatment Occurring in as little as 3-6 months after trans- modalities to quickly reduce the PCP burden in plantation [1, 2], Pneumocystis jiroveci pneu- transplant patients is crucial. monia (PCP) was associated with a mortality rate as high as 50% [3, 4]. Symptoms of PCP The standard first-line therapy for PCP includes include non-productive cough, low- or high- large doses of sulfa drugs. Although this regi- grade fever, severe dyspnea and hypoxemia. men is effective for some patients, the disease Although airborne transmission is thought to be progresses to severe respiratory failure and the route by which PCP is transmitted, patient- even death in a considerable proportion of to-patient transmission has been reported [5, patients, with even worse prognosis in patient 6], resulting in the recommendation for prophy- on immunosuppressive treatment such as lactic therapy and immunosuppressant do- transplant recipients, than that in HIV patients PCP infections of renal transplant recipients [8]. In addition, significant side-effects have tested in 22 renal transplant recipients with been associated with prolonged large dosage severe PCP following kidney transplantation to trimethoprim and sulfamethoxazole (TMP-SMZ) investigate the outcome and safety of com- therapy. Second-line treatments for PCP, includ- bined application of caspofungin and TMP-SMZ ing clindamycin and primaquine phosphate, as compared with conventional TMP-SMZ mo- pentamidine inhalation, trimetrexate and ato- notherapy. vaquone, and intravenous pentamidine, can be used for severe cases. However, poor tolerance Materials and methods and extensive side-effects have also been noted with these second-line therapies; there- Subjects fore, they are not ideal for clinical practice. Renal transplant recipients, who were diag- In the mammalian lung, P. jiroveci has a bipha- nosed with severe PCP in the First Affiliated sic life cycle that includes asexual (trophic form) Hospital of PLA’s General Hospital between and sexual (cyst form) cycles. TMP-SMZ is September 2004 and October 2009, were active against the trophic form but much less included in the current study. These patients effective to clear the cyst that is encapsulated have had received kidney transplants either in and protected by a thick layer containing mostly our hospital or in other transplant centers. beta-1, 3-glucan; therefore, addition of a sec- Patients that received additional transplanta- ond drug that targets the cyst form may more tions beyond the kidney transplantation, had fully inhibit the life cycle of the organism. an additional infection of other etiologies, or Caspofungin, a new class of antifungals belong- previously had severe chronic pulmonary dis- ing to the echinomycin class, inhibits beta-1, eases were excluded from the present study. 3-glucan synthesis, thereby targeting the prin- Severe pneumonia was diagnosed according to cipal component of the P. jiroveci cyst wall and the diagnosis and treatment guidelines as rec- reducing its integrity [9]. Moreover, because ommended by the Respiratory Disease Branch beta-1, 3-glucan itself can induce inflamma- of the Chinese Medical Association, which are tion, inhibition of its synthesis further reduces based on the Infectious Diseases Society of the pathogenicity of P. jiroveci [10]. America (IDSA) guidelines for the management of community-acquired pneumonia [18] and The efficacy of caspofungin has been shown hospital-acquired pneumonia [19]. All patients using in vivo models of PCP [11, 12]. For exam- in this study have pursued medical help within ple, Powles et al. [12] observed a 90% reduc- 2 days of the initial symptom onset. This study tion in PCP cysts 4 days after caspofungin was approved by the institutional review board monotherapy and a 66% reduction in trophozo- (IRB) of the First Affiliated Hospital of PLA’s ites 21 days after treatment. Therefore, caspo- General Hospital. Informed written consent fungin primarily targets the cyst, which is was obtained from each patient enrolled in the responsible for continuously producing large study. amounts of trophozoites in PCP. Furthermore, a recent in vivo study in mice showed that the Pathogen detection and diagnosis efficacy of caspofungin and TMP-SMX combina- tion therapy was greater than that observed for In addition to chest X-ray (CXR) and/or CT analy- either drug alone [13]. However, the few case sis, pathogen detection was carried out for studies that have assessed the application of patients with fever and suspected lung infec- caspofungin for the treatment of PCP in patients tion after admission. Bacterial and fungal cul- have reported varying outcomes, which may be tures and drug sensitivity tests together with due to the limited number of patients analyzed acid-fast staining of blood, sputum, throat swab [14, 15]. Moreover, analysis of its safety and and midstream urine specimens were per- effectiveness in the treatment of transplant formed routinely. For patients without sputum, recipients is even rarer [16, 17]. Therefore, this secretions were obtained by sputum induction retrospective study examined the hypothesis or fiber optic bronchoscopy or via the artificial that caspofungin and TMP-SMX combination airway (BAL, broncho alveolar lavage). Direct therapy would offer superior efficacy over stan- fluorescence staining of P. jiroveci cysts and dard TMP-SMX treatment. This hypothesis was polymerase chain reaction (PCR) analysis for 1235 Int J Clin Exp Med 2017;10(1):1234-1242 PCP infections of renal transplant recipients the gene encoding the large subunit ribosomal methylprednisolone were reduced step by step RNA in the mitochondrion of P. jiroveci were after symptom relief after which immunosup- also performed. In addition, because the diag- pressive agents were gradually re-adminis- nostic accuracy of determining serum beta-1, tered. 3-glucan for PCP is high [20], beta-1, 3-glucan levels were determined to assess the degree of Outcome analysis infection using a specific antiserum as previ- ously described [21]. Furthermore, serum lac- Routine blood tests and blood biochemistry tate dehydrogenase (LDH) levels were also analyses were evaluated every day to monitor determined to indirectly evaluate PCP as in the complete blood count and kidney function. Vogel et al. [22]. Cytomegalovirus (CMV) DNA In addition, arterial blood gases and oxygen- ation indices (PaO /FiO ) were measured daily was identified by routine PCR amplification of 2 2 the HindII-X fragment region or CMV-specific to detect improvements in the oxygenation IgM detection. index. CXR or chest CT was taken every 2-3 days to observe the range and nature of inflam- Treatment mation. Outcomes were evaluated by a com- bined of variables, including body temperature, Because all patients were immunosuppressed, pulmonary signs, and oxygenation index. delayed treatment may have resulted
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