EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Respiratory tract infections are life-threatening infections in solid-organ transplant recipients that pose risk to the graft and to the patient. This study was undertaken to examine the clinical and microbiological spectrum of pneumonia in renal transplant recipients.
Materials and Methods: Of 400 consecutive renal transplant recipients, 87 recipients (21.8%) were hospitalized between November 2014 and October 2016 with pneumonia. We examined demographic profiles and clinical investigations.
Results: The median age of patients was 38 years (range, 19-72 y). The mean time of presentation after renal transplant was 18 months (range, 1-174 mo). Most patients (80.5%) were on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids; 34% of patients had an induction agent. Chronic hepatitis C and hepatitis B infections were found in 12.6% and 2.2% of patients, respectively, and new-onset diabetes in 19.5% of patients. Fever (88%), cough (87%), shortness of breath (68%), and hypotension (33%) were common presenting symptoms. Diarrhea was the most frequent accompanying symptom, found in 9.2% of patients. Cytopenia and graft dysfunction were present in 38.7% and 80.4% of patients. Among infections, fungal infections were the most frequent (30%) followed by mixed infections (20.7%), tuberculosis (12.6%), bacterial (12.6%), and viral (3.5%) infections. Etiology could not be found in 27.6% patients. Mortality rate was 24.1%, with the highest rates for fungal infections (44%), followed by bacterial (25%) and mixed infections (18%). Presence of hypoxia and hypotension at presentation was associated with increased risk of death, whereas use of induction agents, new-onset diabetes posttransplant, diabetes mellitus, and acute kidney injury were not correlated with death or increased duration of hospital stay.
Conclusions: Pneumonia carries high risk of mortality in renal transplant recipients. Fungal and bacterial infections carry high risk of mortality. Despite invasive investigations, a substantial number of patients had unidentified etiology.

Key words : Fungal infection, Kidney transplant, Tuberculosis

Pneumonia is a frequent complication of renal transplantation and confers high risk of morbidity and mortality. Solid-organ transplant recipients are particularly vulnerable to infections because of treatment with immunosuppressive medications, antirejection therapies, and other coexisting risk factors, such as diabetes mellitus, smoking, and chronic lung disease.¹ Various organisms, including bacteria, viruses, and fungi, can cause pneumonia posttransplant. In addition to common bacterial and viral infections, opportunistic infections like Pneumocystis jirovecii, nocardia, cytomegalovirus, and angioinvasive fungal infections are frequently encountered in these patients. The risk of infection and the type of organism causing pneumonia are dictated by the time that has elapsed since transplant, activation of latent infections, exposure to environmental and nosocomial pathogens, prophylactic therapies, and net state of immunosuppression.^2,3

Transplant recipients often have little or no signs and symptoms of infections and are also more likely to experience life-threatening complications like septicemia, septic shock, and respiratory failure with pneumonia due to immunocompromised state and late presentation. Prompt diagnosis and treatment of pneumonia in patients after renal transplant are essential to prevent serious complications, such as sepsis and respiratory failure.^3,4 Evaluation includes meticulous history taking, imaging tests, sputum or bronchoalveolar lavage cultures, and tissue biopsy. Treatment typically involves antibiotics, antiviral agents, or antifungal agents, depending on the type of organism causing the infection. In severe cases, hospitalization may be necessary to monitor and manage oxygenation and cardiorespiratory dysfunction. Prompt diagnosis and timely treatment usually result in patient and graft survival.

Here, we describe profiles of patients after renal transplant who presented to our center and had lower respiratory tract infections.

Materials and Methods

For this retrospective study, we collected data from medical records of all consecutive renal transplant recipients hospitalized with pneumonia in our center between November 2014 and October 2016 (N = 400), after clearance from the Institutional Ethics Committee. The study was conducted in accordance with the 1975 Helsinki Declaration. Patients provided written consent for access to medical records before the start of the study. We collected patient demographic data, including age, sex, basic kidney disease, type of donor, time elapsed since transplant, immunosuppression (including induction agents), maintenance immunosuppression, antirejection therapies, estimated glomerular filtration rate before presentation, cytomegalovirus (CMV) immunoglobulin G status, presence of new-onset diabetes after transplant, and other comorbid conditions. Presenting complaints and clinical signs (including hypoxia and hypotension) were noted. Routine blood work (including complete blood counts, kidney and liver function test), C-reactive protein level, polymerase chain reaction results for CMV, sputum and tissue cultures, radiology, and invasive tests like bronchoscopy were noted. We also noted treatment details, duration of therapy, and associated risk factors, if any.

Statistical analyses

We used descriptive statistics for background variables. Frequencies are shown as percentages. Categorical variables are shown as mean ± SD or median and interquartile range as appropriate. We used the Fisher exact or chi-square tests for categorical variables and t-tests for continuous variables. Regression analysis was used to identify risk factors for poor clinical outcome. P < .05 was considered significant.

Among 400 renal transplant recipients, 87 (21.8%) were hospitalized with infections in our center during the study period. The mean age of patients was 38 ± 11 years; female patients constituted 22% (n = 19) of patients in our study. The median time of presentation after renal transplant was 18 months (interquartile range, 31 mo). Most patients (79.3%) were on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids. Induction agents were used in 39% of patients. Chronic hepatitis C and hepatitis B infections were found in 12.6% and 2.2% of patients, respectively. Nineteen patients (22%) had diabetes mellitus and 19.5% had new-onset diabetes after transplant (Table 1).

Fever (88%) and cough (87%) were the most common presenting symptoms, followed by shortness of breath (68%). Other system involvement was present in 29% (25/87) of patients. Diarrhea was the most frequent accompanying symptom, found in 9.2% of patients. Hypotension and hypoxia at presentation were seen in 33% and 59% of patients and cytopenias and acute kidney injury in 38.7% and 80.4%. Bronchoscopy was performed in 43.4% of patients with diagnostic yield of 37%. Fine needle aspiration was done in 30% of patients with yield of 57.8% (Table 2).

Fungal infections were the most frequent (22.9%), followed by mixed infections (20.6%), tuberculosis (12.6%), bacterial infections (12.6%), and viral infections (3.5%). Cause of infection could not be found in 27.6% of patients despite invasive tests. Of the fungal infections, aspergillosis (30%) and mucormycosis (30%) were the major causative organisms, followed by Pneumocystis jirovecii (25%), cryptococcus (10%), and phaeohyphomycosis (5%).

Mortality rate among our patient group was 24.1% (Table 3). Mortality was highest among patients with fungal infections (44%) followed by bacterial (25%). Cause of pneumonia did not determine mortality or graft failure, need for mechanical ventilation, or inotropic support.

Infections remain the Achilles heel of any transplant program and more so in developing countries. Significant morbidity and mortality are associated with infections among solid-transplant patients. Here, we aimed to elucidate the profile of renal transplant recipients who presented to our center with pneumonia and required hospitalization. The burden of infections is high in low-resource settings, and modern immunosuppressive protocols have only further increased the risk of infections. In these patients, a delay in correct diagnosis and inadequate treatment often lead to poor prognosis.

Our study showed prevalence of pneumonia to be around 21.8%. This is similar to a study done by Dizdar and colleagues.⁵ Another study from the Middle East showed prevalence around 13.4%.⁶ A similar study done by Mangalgi and colleagues at the All India Institute of Medical Sciences reported 88 patients with pneumonia over a span of 2 years, which is almost identical to our result.⁷

Our study had a relatively younger group of patients (in the third to fourth decade of life) who received standard immunosuppression regimens. A significant number of patients had additional risk factors, such as new-onset diabetes after transplant and antirejection therapies in the previous 12 months. In our patient group, most infections occurred in the first 2 years posttransplant, with median time of pneumonia posttransplant of 18 months. The absence of prophylaxis with cotrimoxazole, use of T-cell-depleting agent as the predominant induction agent, and coexistent CMV infection, which was seen in 17% of patients in our study, could all influence the timing of pneumonia. Kalra and colleagues in their study conducted in northern India showed that the mean age of patients was 31.6 years and 83% were males, almost 90% received triple immunosuppression, and 27% had acute rejection before pneumonia.⁸ A similar profile was reported by Mangalgi and colleagues, also in north India.⁷ Most episodes of pneumonia occur later posttransplant, with 50% occurring >1 year posttransplant in the study done from Hoyo and colleagues⁹ and 70.4% of episodes occurring at >6 months posttransplant in a multicenter study from Kupeli and colleagues.¹⁰

Fungal infections (30%) were the most common in our study followed by mixed infections (20.7%) and bacterial (12.6%) and tubercular (12.6%) infections. Other studies showed that bacterial infections were the most common, with 29.4% bacterial infections followed by fungal (20.6%) and tuberculosis (23.5%) in one study and mixed infections seen in 35.2% in another study.^9,10 Several Indian studies also reported that bacterial infections are the most frequent cause of pneumonia.^13-15 A large retrospective study of 217 episodes of pneumonia after solid-organ transplant reported bacterial infections as the most frequent cause of pneumonia, which is again similar to findings reported in many western studies.^9,10,14-16 The predominance of fungal infections could be because our study only included patients who were hospitalized, and most nonserious respiratory infections, likely bacterial, were treated on an out-patient basis in our center. In addition, our hospital is a referral center for larger area in northern India. However, presence of fungal infections was similar to that shown in earlier studies from our center and other studies from India.^7,8,13-16 In another study from our center, the incidence of fungal infections was 10.2% among transplants studied over 3 years.¹⁷

The etiologic diagnosis often requires invasive tests; even after several investigations, the cause may remain elusive in a substantial proportion of patients.^18,19 In our study, invasive diagnostic tests, such as bronchoscopy, transbronchial lung biopsy, fine needle aspiration cytology, and transbronchial lymph node aspiration, were performed in more than 50% of patients. Despite aggressive investigation of our patients, cause could not be determined in 27.6% of patients. Other studies done in India and other countries reported rates of unidentified etiologies of 6% to 30% after invasive tests.²⁰ It is well known that invasive tests, such as bronchiolar lavage culture, increase the yield of etiologic diagnosis. In our study, the best yield was given by computed tomography-guided fine needle aspiration cytology followed by bronchoalveolar lavage cultures and lung biopsies. Bronchoalveolar lavage cultures yielded reason for infection in 75% in another study.⁵ Bronchoalveolar lavage cultures and lung biopsies have also resulted in a diagnosis rate of 64% and 64.7%, respectively.⁷

Pneumonia has a poor prognosis in solid-organ transplant recipients, especially if patients require hospitalization. Death occurred in about a quarter of patients in our study. Other poor clinical outcomes included graft dysfunction in 80.4% of patients and graft failure in 4.5%. Almost 40% of patients required mechanical ventilation, and one-third of patients needed inotropic support, signifying that pneumonia is a life-threatening infection in a significant proportion of patients. Other Indian studies reported mortality rates of 22.7% and 22.5%.^7,8 Western studies reported mortality rates of 20% to 25%.^14-16 Rates of mechanical ventilation and inotropic support were reported as 17.7% and 21.5%, respectively. in the study from Mangalgi and colleagues.⁷

Our study had some limitations. First, it was a descriptive study with a small sample size. Second, our center treats many patients who have undergone transplant in institutes across the country, and baseline demographic data were not available for all patients. Third, our study exclusively involved only hospitalized patients with pneumonia, and hence reported results may not be comparable to other studies.

In conclusion, pneumonia after renal transplant is a serious illness and carries a high risk of mortality and is associated with graft dysfunction. Use of invasive tests can increase the likelihood of identifying the causative organism.

Volume: 22 Issue: 1 January 2024 - Supplement - 1

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