A Rare Case of Concurrent Tropheryma Whipplei and Pneumocystis Jirovecii Pneumonia in a Patient During Endocrine Therapy for Breast Cancer.

Introduction
The combination of ovarian function suppression (OFS) and an aromatase inhibitor (AI) is a cornerstone of adjuvant therapy for high-risk premenopausal women with hormone receptor-positive breast cancer. While its anti-neoplastic efficacy is proven, its systemic immunologic impact is often overlooked. Estrogen exerts pleiotropic effects on immune function, influencing T-cell differentiation,1–4 B-cell activity,5–7 and macrophage polarization.1,7–15 Pneumocystis jirovecii (PJ) is strongly associated with adaptive immune deficiencies, particularly CD4+ T-cell depletion,16,17 while Tropheryma whipplei (TW) infections are more reliant on innate immune dysfunction, such as impaired macrophage activity.18,19 Estrogen’s effects on immunity may further modulate these risks. Profound and sustained estrogen deprivation may create a state of functional immunoparalysis, increasing susceptibility to PJ and TW. While Pneumocystis jirovecii pneumonia (PJP) has been reported in association with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combination with endocrine therapy,20–23 and TW infection remains rare in immunocompetent hosts,19,24,25 their simultaneous occurrence has never been reported in a patient on OFS+AI therapy. This case breaks new ground in understanding the hidden risks of long-term endocrine therapy.

Case Presentation

Patient Information
A 50-year-old female with a history of breast cancer surgery, chemotherapy, endocrine therapy and no smoking history was found to have solid pulmonary nodules incidentally found on chest computed tomography (CT). Chest CT showed left lower lobe posterior basal segment nodule measuring up to 1.8 cm x 1.2 cm in size and associated with surrounding ground-glass pattern, shown in Figure 1A and B. She denied cough, wheezing, fevers, chills, night sweats, or weight loss. Laboratory investigations revealed hemoglobin of 13 g/dl; white blood cell counts of 7.37×109/L with 52.97% neutrophils, 43.30% lymphocytes; and, platelets of 242×109/L. Blood chemistry showed blood urea nitrogen of 3.1 mmol/L and creatinine of 39 umol/L. Her liver function tests were within normal ranges. The remainder of the examination was unremarkable. Initial serologic evaluation for endemic mycosis (Histoplasma, Coccidioides) and Mycobacterium tuberculosis was negative. (1-3)-β-D-glucan level was negative. Furthermore, there was no serologic evidence of Cryptococcus infection. The workup for a potential underlying connective tissue disease was also unremarkable, with negative assays for antinuclear antigen and rheumatoid factor. Pulmonary function testing revealed mild airflow obstruction, which was non-responsive to bronchodilators.After the second day of hospitalization, the patient subsequently consented to bronchoscopy for etiological confirmation, which revealed no significant endobronchial abnormalities, shown in Figure 2. Bronchoalveolar lavage fluid (BALF) was sent for mNGS, identifying TW (sequence count: 3819) and PJ (sequence count: 273). Following a multidisciplinary discussion, this case presents a rare instance of mixed pulmonary infection with TW and PJ. We started a therapy with intravenous ceftriaxone (2.0g intravenously [IV] once daily) for one week and oral sulfamethoxazole-trimethoprim (SMZ-TMP, 0.48g per tablet, two tablets two times daily). After 4 weeks of oral SMZ-TMP, a follow-up chest CT scan demonstrated resolution of the lung lesions, shown in Figure 1C and D.

History
Over six years ago (at age 43), the patient had undergone modified radical mastectomy of the left breast due to a diagnosis of cancer of the left breast. The postoperative pathology results from that procedure supported a diagnosis of left-sided infiltrating ductal carcinoma of the breast, with 0/24 positive axillary lymph nodes. Immunohistochemistry (IHC) results for the primary tumor were as follows: strong positive estrogen receptor (ER), weak positive progesterone receptor (PR), Ki67: 40%, and negative human epidermal growth factor receptor 2(HER2). She received docetaxel + cyclophosphamide for 4 cycles, followed by toremifene for one year. One year later, the development of metastatic disease to the pelvis, sacrum, and sacroiliac joint prompted an adjustment to her endocrine regimen. She was switched to a combination of letrozole (2.5 mg daily) and goserelin (3.6 mg subcutaneously every 28 days) for ovarian function suppression, which she continues to receive.

Discussion
Pneumocystis jirovecii serve as opportunistic pathogens, emerging in immunocompromised individuals.26,27 PJP is a life-threatening opportunistic infection affecting immunocompromised individuals, notably solid organ or hematopoietic stem cell transplant recipients, patients with human immunodeficiency virus (HIV) or hematological malignancies, as well as those receiving glucocorticoids, chemotherapy, or other immunosuppressive therapies.28 Whipple’s disease is a rare, chronic systemic illness caused by TW. It most commonly presents with gastrointestinal symptoms, despite its potential to disseminate to other organ systems.29 We describe an unusual case of PJ and TW co-infection in a patient during endocrine therapy for breast cancer. Six years ago, the patient was diagnosed with breast cancer and underwent surgical treatment followed by chemotherapy. The patient received toremifene for one year. Upon disease progression, her regimen was switched to combined ovarian suppression (goserelin) and an aromatase inhibitor (letrozole), which she has continued to the present. The patient has been using ovarian suppression and aromatase inhibitor therapy for the past 5 years. Although PJP has been reported with CDK4/6 inhibitors,20–23 their simultaneous occurrence has never been reported in a patient on OFS+AI therapy. This case breaks new ground in understanding the hidden risks of long-term endocrine therapy. The primary mechanism of OFS+AI therapy is the profound suppression of endogenous estrogen to inhibit tumor proliferation. However, estrogen is a known immunomodulator, influencing T-lymphocyte function, macrophage activity, and other immune parameters.1,11,14,15 It exhibits a dual immunologic role: while it can potentiate B-cell-mediated humoral immunity, sustained hypoestrogenism has been linked to an impaired Th1-cell response, dysregulation of regulatory T-cells, and altered macrophage phagocytosis. In patients with malignant tumors, the impairment of immune defenses substantially elevates the risk of pneumonia, increases susceptibility to opportunistic infections, and promotes the reactivation of latent pathogens.30,31 Furthermore, the incidence of atypical pathogens is notably higher in this population. Given this immunologic context, the emergence of unexplained respiratory symptoms or imaging abnormalities in patients on OFS+AI should prompt clinicians to broaden their differential diagnosis beyond community-acquired pneumonia to include atypical opportunistic infections.
On the other hand, the diagnosis of both TW and Pneumocystis jirovecii poses a significant challenge for conventional microbiological techniques, including sputum and BALF cultures and smears.26,32 Diagnosing TW is complicated by its fastidious growth requirements, which necessitate prolonged culture cycles and are complicated by a high risk of contamination, often yielding inconclusive results.33 In this case, mNGS provided a definitive TW sequence count that, when correlated with the clinical symptoms, established TW as a primary pathogen. This highlights the pivotal role of mNGS in diagnosing TW pneumonia, thereby enabling targeted treatment in a setting where evidence-based guidelines are absent. Compared to TW, the diagnosis approach for PJP is more well-established. The diagnosis of PJP should be considered in patients with risk factors for PJP who present with pneumonia and suggestive radiographic findings. However, the nonspecific clinical and radiological presentation makes clinical diagnostic challenging. Additionally, Pneumocystis jirovecii does not grow in routine culture media, which presents diagnostic challenges in the laboratory as well. mNGS and targeted next-generation sequencing (tNGS) have emerged as prominent tools.34 In the present case of a rare mixed pulmonary infection with TW and PJ, this diagnostic limitation was overcome by the application of mNGS of BALF. This advanced technique provided a definitive diagnosis, which in turn facilitated the prompt initiation of targeted antimicrobial therapy. After 4 weeks of oral SMZ-TMP, a follow-up chest CT scan performed demonstrated absorption of the lung lesions, highlighting the necessity for bronchoscopy and mNGS examination in cases of complex pulmonary infections.

A systematic literature search was performed using the PubMed database, restricted to English-language publications. The search period extended from the database’s inception through November 2025, employing the specific search strategy: “((Tropheryma whipplei) AND (Pneumocystis jirovecii)) AND (Pneumonia)”. Following article retrieval, a rigorous screening process was implemented, involving evaluation of titles, abstracts, and full texts to exclude non-relevant studies. Only publications definitively documenting pulmonary infections involving both Tropheryma whipplei and Pneumocystis jirovecii were retained for detailed analysis. This selection process yielded two eligible studies that met all inclusion criteria (Table 1). Reports of co-infection with TW and PJ remain scarce, which were primarily concentrated among patients with HIV infection.35,36 No universally standardized therapeutic regimen currently exists. In vitro susceptibility testing of TW using cell culture and real-time polymerase chain reaction assays has demonstrated activity for multiple antibiotic classes, including doxycycline, cephalosporins, macrolides, and TMP-SMX. However, the optimal clinical regimen remains uncertain.19 A prospective trial of 40 European patients with Whipple’s disease demonstrated a 100% clinical and histologic remission rate at one year. All patients received a 14-day induction with either ceftriaxone or meropenem, followed by oral TMP-SMX.37 However, many studies recommend TMP-SMX as the treatment of choice for PJP of any severity in patients without HIV.28,38–41 In light of the clinical presentation, the patient was managed with ceftriaxone and TMP-SMX. Follow-up imaging showed marked improvement in the pulmonary infiltrates. This case report has several limitations. A singular case report is insufficient to establish a causal association between OFS+AI and infection. The lack of immune function monitoring at the time of admission constrained the capacity to definitively confirm immunosuppression attributable to endocrine therapy. TW identified via mNGS may reflect colonization rather than active infection in certain individuals. The absence of standardized diagnostic thresholds for TW infection currently poses a limitation in clinical practice.

Conclusion
We describe a novel case of concurrent TW and PJ in a patient receiving goserelin and letrozole for hormone receptor-positive breast cancer. Diagnosis was ultimately achieved through mNGS of BALF, which provided critical pathogen identification after conventional methods proved non-diagnostic. The patient demonstrated marked clinical and radiological improvement following targeted antimicrobial therapy. This case expands the spectrum of infectious risks associated with modern breast cancer management and underscores the indispensable role of advanced diagnostic techniques in evaluating complex pneumonias in immunocompromised hosts. These findings advocate for heightened clinical vigilance for atypical pathogens in patients receiving potent endocrine therapies, even in the absence of conventional immunosuppressive agents.