Objectives: Kidney transplant represents a major therapeutic advance for end-stage renal disease, but chronic immunosuppression compromises host defense mechanisms, rendering recipients vulnerable to serious infections. Pulmonary infections constitute a major cause of morbidity and mortality posttransplant, requiring vigilant surveillance and multidisciplinary management.
Materials and Methods: This retrospective descriptive study included patients who underwent kidney transplant at the Nephrology Department of Sahloul University Hospital from November 1, 2007, to December 31, 2024, in whom pulmonary involvement was diagnosed during follow-up.
Results: Among 332 kidney transplant recipients, 12 patients (3.6%) developed pulmonary infections. The mean age was 34.5 ± 11.6 years (range, 18-53 years) with male predominance. Chronic interstitial nephropathy was the most common original kidney disease (66.6%). All patients received thymoglobulin induction with methylprednisolone; the main maintenance immunosuppression comprised tacrolimus (83.3%) and mycophenolate mofetil (91.7%). All patients received Pneumocystis jirovecii prophylaxis. Mean serum creatinine at diagnosis was 142.8 ± 70.1 μmol/L (range, 70-262 μmol/L), compared with baseline mean of 63.1 ± 9.9 μmol/L (range, 48-78 μmol/L). Acute kidney injury occurred in 7 patients (58.3%). Mean time to pulmonary involvement was 29.3 ± 23.8 months. The most frequently isolated pathogen was Pneumocystis jirovecii (41.6%), followed by Aspergillus species (25%), Mycobacterium tuberculosis (16.7%), coinfection with Candida albicans (33.3%), and cytomegalovirus infection (16.7%). Immunosuppression was reduced in all cases. Evolution was favorable with targeted therapy in 83% of cases; 1 patient (8.3%) died after intensive care unit transfer.
Conclusions: Prevention of severe pulmonary infections requires optimization of prophylaxis strategies and individualized adaptation of immunosuppressive regimens. Close collaboration with infectious disease specialists and pulmonologists is essential for effective multidisciplinary management. Key words: Immunosuppression, Kidney transplantation, Opportunistic infections, Pneumocystis jirovecii, Pulmonary infections, Transplant complications

Introduction
Kidney transplantation has revolutionized the management of end-stage renal disease, offering superior survival, quality of life, and cost-effectiveness compared with long-term dialysis.^1,2 However, the life-saving immunosuppressive therapy required to prevent allograft rejection creates a state of chronic immunocompromise, fundamentally altering the host’s ability to combat infectious pathogens.³ Infections remain one of the leading causes of morbidity and mortality following kidney transplant, accounting for approximately 20% to 30% of deaths in transplant recipients.^4,5 Pulmonary infections represent a major challenge in posttransplant care due to their frequency, severity, and potential for rapid clinical deterioration.^6,7 The respiratory system is uniquely vulnerable in immunocompromised hosts for several reasons. First, the lungs are continuously exposed to the external environment, encountering potential pathogens with each breath. Second, immunosuppressive medications impair multiple components of pulmonary defense mechanisms, including alveolar macrophage function, mucociliary clearance, and T-cell-mediated immunity.^8,9 Third, the spectrum of potential pulmonary pathogens in transplant recipients extends far beyond community-acquired organisms to include opportunistic fungi, atypical bacteria, viruses, and reactivated latent infections such as tuberculosis.^10,11 The balance between adequate immunosuppression to prevent rejection and minimize infection risk remains delicate, particularly when treating established infections.^12,13 Furthermore, the clinical presentation of pulmonary infections in immunocompromised hosts may be atypical, leading to diagnostic delays and worse outcomes.¹⁴ Data regarding pulmonary complications in kidney transplant recipients from North African populations remain limited. Understanding the local epidemiology, etiological spectrum, risk factors, and outcomes is crucial for developing region-specific prevention strategies and management protocols.

Materials and Methods
This retrospective descriptive study was conducted at the Nephrology Department of Sahloul University Hospital, Sousse, Tunisia, a tertiary care center serving as a regional referral facility for kidney transplantation. The study included all patients who underwent kidney transplant between November 1, 2007, and December 31, 2024 (17-year period). All patient data were handled confidentially, and no identifiable personal information was accessed or disclosed. Inclusion criteria were the diagnosis of opportunistic pulmonary infection confirmed by clinical, radiological, and/or microbiological criteria during posttransplant follow-up; complete medical records with adequate documentation of clinical course; and minimum follow-up of 6 months postinfection. Exclusion criteria were having pulmonary complications of noninfectious etiology (pulmonary edema, malignancy, drug toxicity without infection) and nonopportunistic infections.

Data collection
Data were systematically extracted from electronic medical records, paper charts, radiology reports, microbiology databases, and pathology records. A standardized data collection form was used to ensure consistency. We collected demographic characteristics, including age, male/female sex, body mass index, smoking history, comorbidities (eg, diabetes, hypertension), end-stage renal disease etiology, and pretransplant dialysis details. The collected transplant-related variables included donor type, age and sex, HLA mismatches, induction and maintenance immunosuppression protocols, prophylaxis protocols, and pulmonary infection characteristics (time from transplant to symptom onset, presenting symptoms, severity, intensive care unit admission and duration, mechanical ventilation). For laboratory findings, we collected complete blood count, C-reactive protein level, serum creatinine level at infection diagnosis, and bacteriological findings. For radiological findings (chest radiograph and computed tomography [CT] scan), we collected data on antimicrobial therapy, presence or not of immunosuppression modification, and final outcomes (clinical response to therapy, resolution of symptoms, graft loss, and overall mortality during follow-up).

Statistical analyses
We used descriptive statistics to summarize patient characteristics and outcomes. We expressed normally distributed continuous variables as mean ± SD and categorical variables as frequencies and percentages. We performed comparative analyses between patients with pulmonary infections (group 1) and those without infections (group 2). For statistical tests, we used t test or Mann-Whitney U test for continuous variables and χ2 test or the Fisher exact test for categorical variables. P < .⁰⁵ was significant. We used SPSS version 25 for analyses. Given the small sample size of pulmonary infection cases (n = 12), statistical power for multivariable analyses was limited. Therefore, analyses were primarily descriptive with exploratory comparative assessments.

Results
During the 17-year study period (November 1, 2007, to December 31, 2024), 332 kidney transplants were performed at our center. Pulmonary infections were diagnosed in 12 patients, yielding an overall incidence of 3.6%. The mean age at transplant was comparable between groups: 34.5 ± 11.6 years (range, 18-53 y) in the pulmonary infection group (group 1) versus 33.1 ± 13.3 years in the noninfection group (group 2) (P = .⁷¹⁶). More male (7 patients; 58.3%) than female patients (5 patients; 41.7%) were in group 1, although male predominance was more pronounced in group 2 (65.2%) (P = .⁶²⁹). Comorbidities and baseline risk factors differed notably between groups. Diabetes mellitus affected 8.3% of patients in group 1 versus 4.9% in group 2. Hypertension was less prevalent in group 1 (33.3%) compared with group 2 (66.5%). Mean body mass index was slightly lower in group 1 (21.3 ± 4.3 kg/m²) than in group 2 (22.7 ± 4.6 kg/m²) (P = .³⁸⁵). Pretransplant dialysis modality distribution showed differences: in the pulmonary infection group (group 1), 7 patients (58.3%) had hemodialysis, 3 patients (25.0%) had peritoneal dialysis, and 2 patients (17.7%) had preemptive transplantation versus 81.7% having hemodialysis and 18.3% having peritoneal dialysis in group 2 (P = .⁰⁷⁷, P = .¹⁰⁷). Donor characteristics in the 12 patients with pulmonary infection (group 1) included living related donors for 7 patients (58.3%) and deceased donors for 5 patients (41.7%). Mean donor age was comparable between groups (34.5 ± 11.6 years in group 1 vs 33.1 ± 13.3 years in group 2; P = .⁵²³). HLA mismatches averaged 3.33 ± 1.5 in group 2 and 2.91 ± 1.8 in group 2 (P = .⁴⁸⁹). All 12 patients (100%) in group 1 received induction with thymoglobulin plus methylprednisolone boluses versus 64.7% in group 2 (P < .⁰⁰¹). Maintenance immunosuppression comprised tacrolimus in 83.3% of group 1 versus 66.5% of group 2 (P = .⁰⁰¹) and mycophenolate mofetil in 91.7% of group 1 versus 98.2% of group 2 (P < .⁰⁰¹). Cytomegalovirus (CMV) infection occurred in 33.3% of patients in group 1 versus 15.6% of patients in group 2(P = .⁴⁴⁷). All 12 patients (100%) in group 1 received Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole. Mean time from kidney transplant to pulmonary infection diagnosis was 29.3 ± 23.8 months, with a range of 6 to 84 months (7 years). Table 1 lists the baseline characteristics of the 2 groups. Among 12 pulmonary infection cases, Pneumocystis jirovecii pneumonia (PJP) occurred in 5 patients (41.7%), with candidiasis co-infection in 1 case. Invasive aspergillosis was shown in 3 patients (25.0%), 2 with associated candidiasis. Tuberculosis was diagnosed in 2 patients (16.7%), 1 with candidiasis. The remaining 2 cases (16.7%) involved CMV-related pneumonia. Immunosuppression was reduced in all cases. At pulmonary infection diagnosis, mean serum creatinine was 142.8 ± 70.1 μmol/L (range, 70-262 μmol/L), compared with baseline mean of 63.1 ± 9.9 μmol/L (range, 48-78 μmol/L). Acute kidney injury occurred in 7 patients (58.3%). Figure 1 and Figure 2 show examples of chest CT scans in our cohort. Initial empirical antibacterial therapy comprised ofloxacin, teicoplanin, imipenem-cilastatin, and trimethoprim-sulfamethoxazole (Bactrim), subsequently tailored to identified pathogens: caspofungin for candidiasis, isavuconazole (or voriconazole) for aspergillosis, trimethoprim-sulfamethoxazole for PJP, and multidrug anti-tuberculosis therapy for tuberculosis. Clinical evolution was favorable with targeted therapy in 10 cases (83.3%). Two patients (16.7%) required intensive care unit transfer; only 1 patient (8.3%) died after intensive care unit care. One patient developed septic cerebral emboli and convulsive seizures but ultimately improved.

Discussion
Our study identified pulmonary infections in 3.6% of kidney transplant recipients over a 17-year period, with a mean time to infection of 29.3 months posttransplant. This finding aligns with contemporary literature demonstrating that respiratory infections remain a significant cause of morbidity and mortality in solid-organ transplant recipients, despite advances in prophylaxis and immunosuppressive management.^15,16 Although pulmonary infections are relatively infrequent compared with other posttransplant complications, they carry substantial clinical effects with high mortality rates.¹⁷ Furthermore, age emerges as an important risk factor, with age independently associated with mortality (hazard ratio = 6.21, P = .⁰²).¹⁶ Invasive fungal infections, although less common than bacterial or viral pneumonias, are particularly lethal, with multiple centers reporting low detection rates but high mortality when identified.^17,18 Pneumocystis jirovecii pneumonia was the most frequently identified pathogen in our cohort, affecting 41.6% of patients with pulmonary infections. This finding is consistent with global reports identifying PJP as one of the leading opportunistic infections in kidney transplant recipients despite widespread prophylaxis implementation.^19,20 Recent studies have identified several key risk factors that predict PJP development and poor outcomes. Lymphopenia emerges as a critical biomarker.²¹ Biologic agents, particularly rituximab, have been implicated in late-onset PJP cases occurring after cessation of prophylaxis, likely due to prolonged B-cell depletion and altered immune reconstitution.²² All patients in our cohort received Pneumocystis jirovecii prophylaxis, yet breakthrough infections occurred, raising questions about prophylaxis duration, adherence, and identification of patients requiring extended coverage. Trimethoprim-sulfamethoxazole remains the gold standard for PJP prophylaxis, with established efficacy in preventing infection when administered consistently.^23,24 The optimal duration of PJP prophylaxis remains debated. Traditional protocols recommend 6 to 12 months of prophylaxis posttransplant, corresponding to the period of maximal immunosuppression. However, recent population-based studies comparing short-duration (≤9 months) versus long-duration (>9 months) prophylaxis strategies have yielded mixed results, with some centers reporting late-onset cases after prophylaxis discontinuation.¹⁵ This observation suggests that certain high-risk subgroups may benefit from extended or even lifelong prophylaxis, particularly those receiving lymphocyte-depleting agents, those with recurrent rejection requiring augmented immunosuppression, or those with persistent lymphopenia. Early and accurate diagnosis of PJP is critical for improving outcomes, yet conventional diagnostic methods have limitations. Recent advances in molecular diagnostics have transformed the diagnostic landscape. Metagenomic next-generation sequencing (mNGS) has increased detection sensitivity compared with conventional methods, facilitating earlier treatment initiation.^25,26 The ability to simultaneously detect coinfections and characterize the complete respiratory microbiome represents an additional advantage of this technology, particularly given emerging evidence that respiratory coinfections affect PJP outcomes in solid-organ transplant recipients.²⁷ Among infected kidney transplant recipients, PJP remains a major cause of mortality. In our series, 1 patient with PJP infection (8.3%) died after transfer to the intensive care unit, reflecting the severity of this infection. Aspergillus species accounted for 25% of pulmonary infections in our cohort, representing the second most common pathogen identified. Invasive aspergillosis in kidney transplant recipients is a life-threatening complication associated with high mortality rates, often exceeding 50% in some series.^11,17 Risk factors for invasive aspergillosis in kidney transplant recipients include high-dose corticosteroids, lymphocyte-depleting induction therapy, neutropenia, CMV disease, recent bacterial pneumonia requiring broad-spectrum antibiotics, and environmental exposures to Aspergillus spores during construction or renovation activities.^11,28 Diagnosis of invasive aspergillosis remains challenging due to the nonspecific clinical and radiographic presentation and the difficulty of obtaining definitive microbiologic or histopathologic confirmation.²⁹ The ability of mNGS to detect fungal pathogens directly from blood or respiratory samples without requiring culture represents a significant advance, particularly for difficult-to-culture or fastidious organisms.³⁰ Management of invasive aspergillosis requires prompt initiation of antifungal therapy, typically with voriconazole or isavuconazole as first-line agents, along with careful adjustment of immunosuppression.²⁸ The treatment of invasive fungal infections in transplant recipients is complicated by significant drug-drug interactions between triazole antifungals and immunosuppressive medications, particularly calcineurin inhibitors (tacrolimus, cyclosporine) and mammalian target of rapamycin inhibitors (sirolimus, everolimus).³¹ There is a frequent need for dose reductions of 50% to 90% and intensive therapeutic drug monitoring to prevent toxicity while maintaining adequate immunosuppression to protect the allograft.³¹ The strategy of immunosuppression reduction during active fungal infection must be carefully individualized, balancing the need to improve host defense against the risk of precipitating acute rejection. In our series, immunosuppression was reduced in patients with pulmonary infection, with favorable evolution in 83% of patients, suggesting that this approach can be implemented safely with appropriate monitoring. Mycobacterium tuberculosis accounted for 16.7% of pulmonary infections in our cohort, reflecting the importance of tuberculosis as an opportunistic infection in kidney transplant recipients. Solid-organ transplant recipients have a substantially elevated risk of tuberculosis compared with the general population, with reported incidence rates 20 to 74 times higher in endemic regions.^32,33 The increased tuberculosis risk in transplant recipients results from reactivation of latent tuberculosis infection in the setting of immunosuppression, although primary infection or reinfection can also occur. Risk factors for tuberculosis in transplant recipients include origin from or residence in tuberculosis endemic regions, untreated latent tuberculosis infection at the time of transplant, intensive immunosuppression (particularly with high-dose corticosteroids or lymphocyte-depleting agents), diabetes mellitus, malnutrition, and advanced age.^34,35 As a result, pretransplant screening for latent tuberculosis infection is a cornerstone of tuberculosis prevention in transplant candidates. Current guidelines recommend screening all transplant candidates for latent tuberculosis infection using either tuberculin skin testing or interferon-gamma release assays such as QuantiFERON-TB Gold or T-SPOT.TB.³⁶ Treatment of active tuberculosis in kidney transplant recipients requires standard multi-drug anti-tuberculosis therapy, typically with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial intensive phase, followed by continuation phase therapy.^34,35 The management is complicated by drug interactions, particularly between rifampin and immunosuppressive agents. Rifampin, through potent induction of cytochrome P450 enzymes, reduces levels of calcineurin inhibitors and mammalian target of rapamycin inhibitors, necessitating dose adjustments and intensive therapeutic drug monitoring.³⁷ The choice and intensity of immunosuppressive therapy fundamentally shape infection risk in kidney transplant recipients. Our cohort received uniform induction with thymoglobulin and methylprednisolone. Lymphocyte-depleting induction agents such as thymoglobulin (rabbit antithymocyte globulin) provide potent immunosuppression that reduces acute rejection rates but increases infection risk, particularly opportunistic infections.³⁸ With regard to maintenance immunosuppression, systematic reviews have examined associations between different immunosuppressants and specific infection risks. For PJP, the evidence suggests that higher overall immunosuppression intensity, rather than specific agents, drives risk, although previous work has suggested associations with regimens.³⁹ The challenge lies in identifying the minimum effective immunosuppression for each patient that prevents rejection while minimizing infection risk. All patients in our series underwent immunosuppression reduction during treatment of pulmonary infections, with favorable outcomes. This approach is widely practiced but must be carefully individualized. The typical strategy involves temporary reduction (often by 50%) or discontinuation of the antiproliferative agent (mycophenolate or azathioprine), reduction of calcineurin inhibitor target levels, and maintenance of baseline corticosteroids or modest temporary increase to prevent adrenal insufficiency.¹³ The duration of immunosuppression reduction should be guided by clinical response, with gradual reinstitution as the infection is controlled. Close monitoring for rejection during and after immunosuppression reduction is essential, typically including more frequent assessment of renal function and consideration for protocol biopsy in cases of functional deterioration. Vaccination is an important but underutilized preventive strategy in transplant recipients. Ideally, transplant candidates should complete recommended vaccinations before transplant when immune responses are more robust. Posttransplant vaccination responses are blunted by immunosuppression but still provide meaningful protection for many pathogens.⁴⁰ Our study had several limitations inherent to its retrospective single-center design. The relatively small number of infection cases limited statistical power for identifying risk factors and comparing outcomes. The long study period (17 years) encompasses evolution in immunosuppression protocols, diagnostic techniques, and treatment approaches that may affect generalizability. Selection bias may exist if some pulmonary infections were not recognized or diagnosed. The lack of systematic screening bronchoscopy means that some asymptomatic or minimally symptomatic infections may have been missed. Future research directions should focus on several key areas. Comparative effectiveness research examining different prophylaxis strategies, including optimal duration of PJP prophylaxis and role of extended prophylaxis in high-risk subgroups, would inform clinical practice. Studies evaluating novel diagnostic approaches including mNGS in real-world settings are needed to establish clinical utility, cost-effectiveness, and optimal integration into diagnostic algorithms.

Conclusions
Pulmonary infections significantly contribute to morbidity and mortality in kidney transplant recipients, primarily from opportunistic pathogens like Pneumocystis jirovecii, Aspergillus species, and Mycobacterium tuberculosis, despite prevention advances. Early diagnosis demands high suspicion, advanced imaging, bronchoscopy, and molecular techniques; management involves targeted antimicrobials, immunosuppression adjustment, and multidisciplinary care. Prevention relies on prophylaxis, vaccination, screening, and exposure reduction. Ongoing research into diagnostics, risk models, and novel strategies is essential for better outcomes.