Objectives: Complications, which affect the morbidity and mortality of patients after heart transplant, can be divided into infectious and noninfections com-plications. Here, we analyzed both infectious and noninfectious complications and their relation to clinical, laboratory, and surgical characteristics in a Latin American heart transplant population.

Materials and Methods: Data were obtained from records of 35 heart transplant patients in the period from 2010 to 2015. Noninfectious and infectious complications were divided into 3 time intervals: within the first month, from month 2 to 6, and after month 6. Relations between complications and clinical, laboratory and surgical variables in different interval times were analyzed.

Results: In our patient group, 70 infectious and 133 noninfectious complications were reported after heart transplant. Infectious complications occurred more often between months 2 and 6 after heart transplant, whereas noninfectious complications occurred more often during the first month. Bacteria were the most common microorganism, and acute graft rejection was the most common noninfectious complication. Moreover, infectious complications were statistically related to 5 factors at month 1 (intraoperative bleeding, normal postsurgery leukocyte level, mild malnutrition, severe malnutrition, and graft rejection), to 3 factors between months 2 and 6 (diabetes mellitus, stage 2 chronic kidney disease, and cryoprecipitate trans-fusions), and to 2 factors after month 6 (prothrombin time and psychologic diagnosis).

Conclusions: Our results demonstrated that nonin-fectious complications should be anticipated first in patients after heart transplant. In addition, there are characteristics associated with infectious com-plications that can be seen during a specific time period.

Key words : Acute graft rejection, Bacteria, Cardiac transplant, Communicable diseases

Introduction

Heart transplant remains the therapy of choice when previous medical treatments fail to sustain cardiac functions.^1,2 However, despite medical and surgical advances, this surgical procedure still has adversities,³ which can be classified as infectious and noninfectious complications. The former, which is increased because of immunosuppressive therapy, is an important cause of mortality after heart transplant.^4,5 Bacterial infections are more common during the first month after heart transplant, viruses are more common from months 2 to 6, and community-acquired infections are more common after month 6.^6,7 The most common bacteria found are Escherichia coli and Staphylococcus species; on the other hand, Cytomegalovirus is the most common virus found and a major cause of morbidity and rehos-pitalization.8,9 Regarding fungal infections, the most frequent organisms are Candida and Aspergillus species.¹⁰ Regarding noninfectious complications, graft dysfunction and rejection are the main causes of morbidity and mortality.^11,12

Several factors related to increased infections have been identified; these include chronic lung disease, heart failure, elevated creatinine levels, corticosteroid use, left ventricular assist device, a second operation opening the sternum, and longer surgery duration.¹³ In relation to noninfectious complications, pretransplant cardiogenic shock, early endothelial dysfunction, and sex mismatch affect their appearance.^14,15 In addition, patient ethnicity and race also affect the appearance of these complications.¹⁶

Regarding the Latin American population, few studies have been conducted. The ones thus far carried out in this region have focused on infections of a specific cause or on a single therapy outcome, which have used different protocol guidelines.^12,17 In addition, the previous studies did not entirely seek to identify the related characteristics with the development of infectious and noninfectious complications; hence, they did not categorize the complications as they chronically appeared.^7,18,19 Therefore, the aim of this study was to evaluate the infectious and noninfectious complications in a Latin American population after heart transplant. In addition, we sought to assess the related charac-teristics with their appearance over different time intervals to acknowledge how using our own protocol guidelines could result in a different presentation of these types of complications.

Materials and Methods

This was a retrospective and analytical study, which was approved by our institutional review board. Data were obtained by reviewing the medical records of all 35 patients who underwent heart transplant between 2010 and 2015 at our center. The surgical procedure was performed at the “Instituto Nacional Cardiovascular” (Lima, Peru), which is the national reference institute for heart transplant in Peru. The demographic and clinical characteristics of the donors could not be analyzed, as these data were not provided from medical records or by the institution.

Heart transplant procedures
All heart transplants were carried out by the Instituto Nacional Cardiovascular Management Guide. The recipients received grafts from deceased donors, and the surgical technique used for this procedure was the one-lung orthotopic bicaval procedure. Before transplant, each recipient underwent an evaluation of serologic status and presence of infections and previous colonizations. In addition, histocompatibility with the donor was analyzed. Induction therapy comprised basiliximab and methylprednisolone for corticotherapy, which was initially given and which then continued with prednisone. For antibacterial prophylaxis, 1 g of cefepime was given intravenously every 8 hours for 7 days, as long as there was no previous complication that required another drug. After transplant, patients received an immunosup-pressive triple therapy, consisting of mycophenolate mofetil, tacrolimus, and corticosteroids. To prevent cytomegalovirus infection, ganciclovir was administered for 1 week and then valganciclovir for 3 months. As an additional prophylactic therapy, patients received trimethoprim/sulfamethoxazole for 1 year; oral nystatin, topical cotrimoxazole, and ciprofloxacin drops were provided only during the period when patients were hospitalized.

Complications and colonization
A multidisciplinary team of different specialists diagnosed the infectious and noninfectious complications. For the purpose of our study, complications were defined as adverse health-related events that occurred after heart transplant. Complications were divided into infectious and noninfectious complications. Infections were defined as ones identified by the health team when a clinically related manifestation of a specific organ or systemic alteration appeared, supported by laboratory and microorganism culture tests. In contrast, noninfectious complications were the diseases confirmed by the health personnel, supported by the clinic, laboratory tests, and endomyocardial biopsy results, with no relation to infectious diseases. When a microorganism was isolated with lack of clinical and laboratory manifestations of a possible infection, it was categorized as a colonization.

Follow-up
During hospitalization, patients were clinically assessed daily. After patient discharge, regular follow-up was conducted every 2 weeks during the first 2 months, monthly between the second and sixth months, and then every 2 to 3 months. Moreover, patients underwent a systematic sequence of laboratory tests and endomyocardial biopsies to evidence graft rejections. Hospitalization occurred when a clinical manifestation of a complication or an abnormality during the medical check was identified. Complications were classified by time period: in the first month, during months 2 to 6, and after month 6.

Statistical analyses
For the sociodemographic and clinical variables, descriptive statistics were used, such as the mean and standard deviation for quantitative variables and frequencies for qualitative variables. Subsequently, bivariate analysis was employed, using the chi-square test for categorical variables and Pearson correlation for normally distributed variables. P < .05 was considered to be statistically significant. All analyses were done using Microsoft Excel and SPSS version 23 for Windows 10 SPSS software (SPSS: An IBM Company, IBM Corporation, Armonk, NY, USA).

Results

Average age of patients was 39.49 ± 15.07 years, and most were male patients (63%). The most frequent antecedent was pulmonary hypertension (71%). Hypertension, diabetes mellitus, and dyslipidemia had a low frequency of occurrence in our population. Regarding cardiovascular history of any kind, a catheterization procedure was the most frequently used (66%). Regarding lipid profile, a large percentage of the population had a total cholesterol (49%) and high-density lipoprotein (69%) level lower than 160 mg/dL and 40 mg/dL. The mean pretransplant and posttransplant ejection fraction was 22.14 ± 3.40 and 64.65 ± 4.30. Postoperative surgical features are listed in Table 1. The average time of surgery was 377.46 ± 136.06 minutes, with aortic clamp time of 111.80 ± 36 minutes and intraoperative bleeding amount of 908.57 ± 627.49 mL.

Clinical variables statistically associated with a higher frequency of infections within the first month included total leukocytes after surgery, mild and severe malnutrition, intraoperative bleeding, and acute graft rejections. From months 2 to 6, these variables included diabetes mellitus, chronic kidney disease stage 2, and arrhythmias. Regarding infections after the sixth month, the only variables significantly associated were prothrombin time and psychologic diagnoses (Table 1).

There were 1.02 ± 1.54 colonizations per patient in general. In addition, the colonizations within the first month and between months 2 and 6 were significantly associated with infections in their respective period (Table 1). Twelve patients developed colonizations, with 11 between 1 week before transplant and 1 month posttransplant, with 23 colonizations. There were 3 cases of colonizations during months 2 to 6. Regarding infectious com-plications, there were 70 cases, with a mean of 2.00 ± 1.94 per patient. Thirteen were within the first month, 16 in the interval from months 2 to 6, and 10 after month 6 posttransplant. In general, the ones involving the respiratory system were the most common (33%), followed by systemic infections (25.7%). Most infections (51.4%) occurred between months 2 and 6 after heart transplant (Table 2).

In our patient group regarding infectious complications, 49 microorganisms were isolated: 35 of them corresponded to bacteria (71.5%), 6 were viral agents (12.2%), 5 were parasites (10.2%), and 3 were fungi (6.1%). With respect to the classification of occurrence, there was an increased frequency of microorganisms between months 2 and 6 (31/49), of which the most common corresponded to bacteria with 22 microorganisms (71.0%). A lower frequency of isolated microorganisms was found after month 6 posttransplant. In addition, we observed that the most common bacteria were Escherichia coli (20%) followed by Pseudomonas aeruginosa (16.3%) and Klebsiella species (14.3%). With respect to viruses, cytomegalovirus and influenza viruses predominated with 2 copies each, whereas fungi (Aspergillus fumigatus) comprised 6.1% (Table 3).

Table 4 presents the 133 noninfectious com-plications in our population. Among these, cardio-vascular complications were the most frequent (48.9%). The largest number was during the first month (57.9%), whereas the lowest occurrence was after month 6 (23 complications, 17.3%). Importantly, the most frequent complication was acute graft rejection (29 cases, 21.8%); these occurred mostly between months 2 and 6 after heart transplant. On the other hand, the second most common complication was pericardial effusion (26 notifications, 19.5%), which occurred mostly in the first month (25 notifications, 18.8%).

Discussion

Our results reported here demonstrated the distribution and the related characteristics of the infectious and noninfectious complications after heart transplant in a local Latin American population. To the best of our knowledge, there are no other current studies that have categorized the distribution of these complications over specified time intervals in this patient population. Our result showed that the noninfectious complications were more frequent than the infections complications. During the first time interval (1 month or less), the most common complication involved the cardio-vascular system in which acute graft rejection was the most frequent complication. Infectious com-plications occurred more often during months 2 to 6 after heart transplant, with the most frequent cause and system involved being gram-negative bacteria and the respiratory system. In addition, several related characteristics were identified in relation to a temporality sequence.

One of these factors was history of diabetes mellitus, which had a relation with infections occurring during months 2 to 6 after heart transplant. The immunosuppressive characteristics of this disease make patients prone to developing infections.²⁰ In a study by Cho and associates,²¹ patients who developed diabetes mellitus after heart transplant had a greater number of infections after the sixth month of the procedure. This study possibly established that a positive history of diabetes mellitus before surgery makes a patient prone to developing infections earlier than expected. Similarly, malnutrition is an immunosuppressive disease due to the loss of proteins involved in the immune response.^22,23 Malnutrition also facilitates the appearance of infectious diseases. In our population, we found a relation between malnutrition and the presence of infections, except in patients with a diagnosis of moderate malnutrition. In addition, the low population number was not sufficient to reach statistical significance. On the basis of these findings, patients with these mentioned conditions should be carefully managed by a specific medical team with all the preventive and medical care strategies required so that adversities can be prevented.

In relation to surgical aspects, increased post-operative bleeding, defined as bleeding that requires 5 or more globular packages in less than 72 hours once the operation is complete, has been shown to be associated with increased morbidity and mortality.²⁴ Moreover, Buchs and associates²⁵ showed that perioperative bleeding of more than 500 mL is a marker for increased mortality. Our study also suggested that intraoperative bleeding is a factor associated with higher frequency of infections in the first month. However, information is lacking to support the pathophysiologic basis of this finding.

Interestingly, individuals with a psychologic-type diagnosis had a higher frequency of infections 6 months after heart transplant. This variable was previously studied by Grady and associates,²⁶ who showed that predictors of quality of life at 1 year after heart transplant were merely psychologic. Our results suggested that psychologic disorders play a role in the development of infections late after heart transplant. Patient lifestyle may have influenced the development of the infections.

The most common complication shown in our results was acute rejection. This is a frequent complication, with one report mentioning that this event was the leading cause of death.²⁷ In our patient group, within the first month, there were 7 acute graft rejections, which were related to a greater number of infections during this period. Immuno-suppressive therapy in this period was the cause of this complication.

The occurrence of infectious diseases after heart transplant can be explained by the immuno-modulatory therapy that the patients received.^4,28 Complications in the first month after transplant are now shown to be mainly due to bacteria.6 In one study, 43.6% of episodes of infections after heart transplant were caused by bacteria, whereas viruses, fungi, and parasites caused 41.7%, 10.2%, and 0.6% of episodes.²⁹ Our study corroborated this finding, showing that bacteria were the most common microorganism of infection (69.4%).

The bacteriologic spectrum in heart transplant patients is mainly due to staphylococci and gram-negative bacteria (Escherichia coli, Pseudomonas species, and Acinetobacter species). In relation to viruses, the most frequent types are herpes simplex virus, Cytomegalovirus, and varicella zoster virus.⁷ One study reported that gram-negative bacteria were the most common (mostly Escherichia coli and Pseudomonas aeruginosa), causing approximately 53% of all bacterial infections. Herpes simplex virus at 23.7%, varicella zoster at 25.1%, and Cytomegalovirus at 14.1% rates of occurrences have been reported.²⁹ These results were similar to ours, in which bacteria caused 71.5% of all infectious episodes, with the most common microorganism being gram-negative (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species). However, we did not find Cytomegalovirus to be a substantial agent in our population, as it had a similar frequency to others virus. Similar to our results, a study carried out in a Latin American population identified only 1 case of cytomegalovirus infection causing pneumonia.¹⁸ Perhaps the characteristics of this population may explain the low prevalence and low spread of this virus after heart transplant. It is noteworthy that, contrary to that reported in the literature, most isolated bacteria were shown within months 2 to 6 after heart transplant. We attribute this to the antibacterial prophylactic therapy with cefepime that is administered to patients at our center.

According to the report of the International Society for Heart and Lung Transplantation, malignant diseases comprise 20% of all cardiac complications after transplant; of these, 20% are caused by skin cancer and 2% by lymphoma in a 10-year period after transplant.³⁰ Nevertheless, in our study we could not find any malignancies in our patient group. We attribute this to 2 main causes. First, our data included only 5 years of follow-up; therefore, it is unlikely that a malignant neoplastic disease would develop within that period. Second, the genetic and environmental factors specific to the population may be responsible for this finding.

The present study has certain limitations. One is the small population studied, due to the low number of transplants performed at our institution. This event probably limited the extrapolation of our results to the Peruvian population, despite ours being the national reference institute for heart transplant. In addition, studies have shown that some specific complications manifest 10 years after transplant.^27,30 Our follow-up was only for 5 years, thus restricting the analysis of possible complications that develop after 5 years. In addition, not all of the microorganisms could be isolated, limiting a deeper analysis. Another limitation was the retrospective design. Hence, we recommend carrying out a prospective study with a rigorous microbiologic control and longer follow-up in a larger population. In addition, there is a need for more research to clarify the scientific basis of our findings.

In conclusion, the results show the importance of evaluating some specific clinical and laboratory characteristics, so that corresponding medical and administrative measures are taken to prevent and to prepare for infectious and noninfectious com-plications in patients after heart transplant. Moreover, noninfectious complications should be anticipated first in heart transplant patients, with a special attention to acute rejection events. Infectious complications are probably delayed by prophylactic treatment.

References:

1. Daga Ruiz D, Fernández Aguirre C, Segura González F, Carballo Ruiz M. [Indications and long-term outcomes for solid organ transplant. Quality of life in solid organ transplant recipients.] Med Intensiva. 2008;32(6):296-303.
   CrossRef - PubMed
   
2. Hullin R. Heart transplantation: current practice and outlook to the future. Swiss Med Wkly. 2014;144:w13977. doi: 10.4414/smw.2014.13977.
   CrossRef - PubMed
   
3. Singh N, Limaye AP. Infections in Solid-Organ Transplant Recipients. In: Blaser JE, ed. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Churchill Livingstone; 2015:3440-3452.
   
   
4. De Gasperi A, Feltracco P, Ceravola E, Mazza E. Pulmonary complications in patients receiving a solid-organ transplant. Curr Opin Crit Care. 2014;20(4):411-419.
   CrossRef - PubMed
   
5. Tallaj JA, Pamboukian SV, George JF, et al. Have risk factors for mortality after heart transplantation changed over time? Insights from 19 years of Cardiac Transplant Research Database study. J Heart Lung Transplant. 2014;33(12):1304-1311.
   CrossRef - PubMed
   
6. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601-2614.
   CrossRef - PubMed
   
7. Snydman DR. Epidemiology of infections after solid-organ transplantation. Clin Infect Dis. 2001;33(Supplement 1):S5-S8.
   CrossRef - PubMed
   
8. Abate D, Fiscon M, Saldan A, et al. Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection. J Clin Microbiol. 2012;50(6):1974-1980.
   CrossRef - PubMed
   
9. Kirklin JK, Naftel DC, Levine TB, et al. Cytomegalovirus after heart transplantation. Risk factors for infection and death: a multiinstitutional study. The Cardiac Transplant Research Database Group. J Heart Lung Transplant. 1994;13(3):394-404.
   PubMed
   
10. Gavaldà J, Meije Y, Fortún J, et al. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect. 2014;20(Suppl 7):27-48.
    CrossRef - PubMed
    
11. Van Bakel AB, Brown RN, Nikolaidis LA, Heroux A, Law K, Naftel DC. Variations in institutional staffing and clinical practice are predictive of center-specific 1-year survival post-transplant. J Heart Lung Transplant. 2013;32(12):1196-1204.
    CrossRef - PubMed
    
12. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13(5):1203-1216.
    CrossRef - PubMed
    
13. Gelijns AC, Moskowitz AJ, Acker MA, et al. Management practices and major infections after cardiac surgery. J Am Coll Cardiol. 2014;64(4):372-381.
    CrossRef - PubMed
    
14. Lopez-Fernandez S, Manito-Lorite N, Gomez-Hospital JA, et al. Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation. Clin Transplant. 2014;28(12):1393-1401.
    CrossRef - PubMed
    
15. Imamura T, Kinugawa K, Nitta D, et al. Late rejection occurred in recipients who experienced acute cellular rejection within the first year after heart transplantation. Int Heart J. 2015;56(2):174-179.
    CrossRef - PubMed
    
16. Morris AA, Kalogeropoulos AP, Zhao L, et al. Race and ethnic differences in the epidemiology and risk factors for graft failure after heart transplantation. J Heart Lung Transplant. 2015;34(6):825-831.
    CrossRef - PubMed
    
17. Godoy HL, Guerra CM, Viegas RF, et al. Infections in heart transplant recipients in Brazil: the challenge of Chagas' disease. J Heart Lung Transplant. 2010;29(3):286-290.
    CrossRef - PubMed
    
18. Aranguiz-Santander E, Merello L, Pedemonte O, Torres H, Vera A, Alburquerque J. Heart transplantation in chile: preliminary report from the Gustavo Fricke hospital in Vina del Mar. Transplant Proc. 2007;39(3):619-621.
    CrossRef - PubMed
    
19. Godoy HL, Guerra CM, Viegas RF, Diniz RV, Almeida DR. Incidence and outcomes of infections in cardiac allograft recipients: A Brazilian perspective. Am J Infect Control. 2010;38(2):162-163.
    CrossRef - PubMed
    
20. Tanaka Y. [Immunosuppressive mechanisms in diabetes mellitus]. Nihon Rinsho. 2008;66(12):2233-2237.
    PubMed
    
21. Cho MS, Choi HI, Kim IO, et al. The clinical course and outcomes of post-transplantation diabetes mellitus after heart transplantation. J Korean Med Sci. 2012;27(12):1460-1467.
    CrossRef - PubMed
    
22. Jones KD, Berkley JA. Severe acute malnutrition and infection. Paediatr Int Child Health. 2014;34(Suppl 1):S1-29.
    CrossRef - PubMed
    
23. Jones KD, Thitiri J, Ngari M, Berkley JA. Childhood malnutrition: toward an understanding of infections, inflammation, and antimicrobials. Food Nutr Bull. 2014;35(2 Suppl):S64-70.
    CrossRef - PubMed
    
24. McCoy CC, Englum BR, Keenan JE, Vaslef SN, Shapiro ML, Scarborough JE. Impact of specific postoperative complications on the outcomes of emergency general surgery patients. J Trauma Acute Care Surg. 2015;78(5):912-918; discussion 918-919.
    CrossRef - PubMed
    
25. Buchs NC, Addeo P, Bianco FM, et al. Perioperative risk assessment in robotic general surgery: lessons learned from 884 cases at a single institution. Arch Surg. 2012;147(8):701-708.
    CrossRef - PubMed
    
26. Grady KL, Jalowiec A, White-Williams C. Predictors of quality of life in patients at one year after heart transplantation. J Heart Lung Transplant. 1999;18(3):202-210.
    CrossRef - PubMed
    
27. Almenar L, Segovia J, Crespo-Leiro MG, et al. Spanish registry on heart transplantation. 23rd official report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2011). Rev Esp Cardiol (Engl Ed). 2012;65(11):1030-1038.
    CrossRef - PubMed
    
28. Wilhelm MJ. Long-term outcome following heart transplantation: current perspective. J Thorac Dis. 2015;7(3):549-551.
    PubMed
    
29. Montoya JG, Giraldo LF, Efron B, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis. 2001;33(5):629-640.
    CrossRef - PubMed
    
30. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10):996-1008.
    CrossRef - PubMed