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Lymphocyte subsets and the increased risk for opportunistic infections in severe restrictive anorexia nervosa

Journal of Eating Disorders volume 13, Article number: 84 (2025) Cite this article

Abstract

Restrictive anorexia nervosa (AN-R) is characterized not only by psychiatric manifestations but also by significant medical complications. Patients commonly exhibit immune alterations, potentially increasing their susceptibility to infections. While direct evidence linking AN-R to heightened rates of opportunistic infections remains inconclusive, clinical observations suggest a higher incidence of complications and delayed febrile response in patients with infections. Concurrently, malnutrition, a frequent cause of secondary immunodeficiencies, exacerbates this susceptibility by compromising immune function. This paper investigates the immunological profiles of two patients with long-term AN-R who developed severe infections: one with disseminated Mycobacterium kansasii and the other with a co-infection of pulmonary Aspergillus fumigatus and Mycobacterium celatum. These cases, alongside data collected from previously published case reports summarized in this study, highlight the impact of altered immune function associated with mentioned population. The paper aims to explain the underlying mechanisms of immune dysfunction. Proactive monitoring of immune status and incorporating such assays into clinical practice may benefit early detection, effective management, and ultimately, improved outcomes.

Introduction

Patients with restrictive anorexia nervosa (AN-R) have significantly elevated mortality rates and are known to have many medical complications [1, 2]. The most common findings include metabolic and serum chemistry abnormalities, severe endocrine dysregulation due to the body's adjustment to a low energy state, such as nonthyroidal illness syndrome, functional hypogonadotropic hypogonadism with subsequent amenorrhea, and decreased bone mineral density, presenting as osteopenia or osteoporosis [3]. Various cardiac abnormalities have been documented [4]. Gastrointestinal issues include weakened pharyngeal muscles, gastroparesis, and superior mesenteric artery syndrome. Neurological complications encompass brain matter atrophy, neurocognitive deficits, and autonomic nervous system dysregulation (e.g. temperature dysregulation).

The immune system is a complex network of cells, tissues, and organs that work together to defend the body against infections and diseases. The innate immune system provides immediate, nonspecific defense mechanisms against pathogens, including physical barriers like the skin, as well as cells like neutrophils and macrophages that engulf and destroy invading microbes. On the other hand, the adaptive immune system, which includes T and B lymphocytes, provides a more targeted response by recognizing specific pathogens and generating antibodies or cell-mediated responses to eliminate such pathogens. In the context of the infections in individuals with anorexia nervosa that we describe in this paper, alterations in both the innate and adaptive immune system may be involved.

Hematological changes are common in patients with AN, with leukopenia being the most frequent, followed by anemia, typically macrocytic rather than microcytic, and thrombocytopenia [5,6,7]. Despite the observed leukopenia, patients with AN-R are not commonly believed to experience an increased rate of infection [8]. However, patients with AN-R who have bacterial infections exhibit a diminished fever response, with infection frequency escalating with age. In comparison to controls, patients with AN and infectious complications are more susceptible to prolonged hospital stays [9]. The immune system in this group of patients is largely understudied.

In the two following clinical cases, we describe in detail the immunological changes of two patients with longstanding AN-R with severe opportunistic infections. The first concerns a pulmonary M. kansasii infection whilst the other had a M. celatum pulmonary infection with concomitant pulmonary Aspergillosis fumigatus. The aim of this paper is to highlight the potential mechanisms that underlie altered immune response in patients with AN-R, with respect to T cells and B cells, emphasizing the importance of closely monitoring this group to predict, prevent, and manage immune disturbances and infectious complications. Additionally, it is clinically relevant to recognize patients who might be susceptible to opportunistic infections in order to prevent severe complications.

Clinical cases

M. kansasii case

A 51-year-old woman with a decades-long history of AN-R, compulsive personality disorder, Turner syndrome, history of transient ischemic attack, osteopenia, secondary amenorrhea and lymphopenia was evaluated at the Emergency Care Department of Amsterdam UMC and then admitted to the Department of Pulmonology due to recent onset dyspnea, hemoptysis and a 9-month-lasting cough without sputum production. She had not noticed any fever and reported no chest pain. The patient had no known history of pulmonary infections requiring treatment.

Physical examination revealed severe underweight (body mass 35 kg, height 167 cm, and body mass index (BMI) of 12.5 kg/m2). The patient's vital parameters were recorded as follows: heart rate of 62 beats per minute, blood pressure of 144/86 mmHg, body temperature 35.5 °Celsius, a respiratory rate of 13 breaths per minute and an oxygen saturation of 95% with 5 L of supplemental oxygen. Clinical examination of the chest and abdomen was unremarkable, as well as auscultation of the heart and lungs. Laboratory investigation revealed anemia (hemoglobin: 6.9 mmol/L), mild leukopenia (4.1 × 109/L), normal platelet count (281 × 109/L), with electrolytes within normal range (sodium 133 mmol/L, potassium 3.6 mmol/L). Her liver enzymes were diffusely elevated without increased bilirubin, CRP was normal and ANCA titers were low. A high resolution CT scan of the chest (Fig. 1) revealed a thick walled, cavitating consolidation at the right upper lobe with surrounding bronchiolitis.

Fig. 1
figure 1

CT chest of patient 1 at the presentation. Thick walled, cavitating consolidation (orange arrow and orange *) at the right upper lobe with surrounding bronchiolitis

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Initial results of cultures of sputum and bronchoalveolar lavage (BAL) fluid showed no pathogens. Because of persistent hemoptysis and uncertainty about the diagnosis, patient underwent uniportal video-assisted thoracic surgery for lobectomy of the right upper lobe, which was complicated by an empyema. Subsequently, cultures of the pleural fluid and the resected tissue were found positive for Mycobacterium.

kansasii. Patient was initially treated with empiric antibiotics (amoxicillin-clavulanic acid), which was changed to the combination of rifampicin, ethambutol, and isoniazid for better coverage of the mycobacterial infection. Pyridoxine was started to prevent neuropathy in addition to thiamine that was prescribed during refeeding. Due to difficulties in obtaining appropriate dosages for the patient's low weight, isoniazid monotherapy was initiated one month later in the treatment course.

Additional laboratory investigation revealed severe deficiency in absolute numbers of B cells (0.004 × 109/L, presenting 0.86% of all lymphocytes). Absolute counts of all T cells (CD3 + 0.318 × 109/L; CD4 + T cells 0.187 × 109/L and CD8 + T cells 0.101 × 109/L) were low. However, percentages of T lymphocytes were within normal values including a normal CD4 + /CD8 + ratio of 1,8. Further immunophenotyping was conducted on B cells, and T cells. No hypogammaglobulinemia was present. Further immunological assessment concluded patient had no known immunological disorder that could explain longstanding lymphopenia and opportunistic infection other than malnutrition. The total duration of treatment for M. kansasii infection was 1 year, and the patient responded to antibiotic treatment with no side effects. Nutritional support was also provided to address her severe malnutrition.

Over the months after admission, the patient showed gradual improvement in nutritional status, evidenced by weight gain and a rise in BMI to 14.0 kg/m2 in 11 months. Laboratory analysis revealed resolution of leukopenia at the time of weight gain. Absolute numbers of T cells normalized, including normalization of CD8 + T cells and CD4 + T cells, and absolute numbers of B lymphocytes normalized (100-fold). NK cell numbers increased. 26 months after admission, the patient lost weight again, her BMI fell to 12.4 kg/m2 and the subgroups of lymphocytes declined in absolute numbers again below reference values (Fig. 2).

Fig. 2
figure 2

Overview of the dynamics of patient 1 BMI and absolute number of subsets of lymphocytes; B cells, all T cells (CD3 +), CD8 + T cells, CD4 + T cells, natural killer (NK) cells over time since start of disease. Lymphocyte subsets are presented in absolute counts measured in whole blood. X-axis shows number of months after admission, left Y-axis lymphocyte counts and the right Y-axis BMI (body mass index) in kg/m2. The reference values are as follows: T cells (CD3 +) range from 0.7 to 2.1 × 109 cells/L, CD4 + T cells range from 0.3 to 1.4 × 109 cells/L, CD8 + T cells range from 0.2 to 0.9 × 109 cells/L, B cells range from 0.1 to 0.5 × 109 cells/L, and NK cells range from 0.09 to 0.6 × 109 cells/L

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M. celatum and A. fumigatus case

A 44-year-old female patient who also had a decades-long history of AN-R, autism spectrum disorder, anxiety/compulsive disorder, spastic colon/irritable bowel syndrome, secondary amenorrhea and osteoporosis presented with cough, hemoptysis and night sweats and was evaluated at another center. Four months prior, she was hospitalized due to severe malnutrition requiring short-term refeeding.

Physical examination revealed severe underweight. Her body weight was 28.5 kg, height 160 cm, and BMI 11.1 kg/m2, with lower limb edema. The patient's vital parameters were: heart rate of 60 beats per minute, blood pressure of 79/63 mmHg, and body temperature of 37 °C.

Laboratory results indicated anemia (hemoglobin 7.0 mmol/L), normal leukocyte count (7,500 × 109/L), and normal platelet count (291 × 109/L). Further laboratory investigation revealed lymphopenia with a total lymphocyte count ranging from 0.48—0.60 cells/109/L. Due to a suspected Mycobacterium tuberculosis infection and abnormalities on her chest CT (Fig. 3), BAL was performed and confirmed the presence of both M. celatum and A. fumigatus.

Fig. 3
figure 3

CT chest of patient 2 in the first months of presentation. Large, bilateral cavitary lesions (orange arrows) with polypoid growth (*) at the right upper lobe. In addition, several dense consolidations / nodules (blue arrows), most present at the left upper lobe and lingula

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A multidisciplinary team decided to prioritize treatment for the A. fumigatus infection above tuberculostatic treatment, as the mycobacterium was deemed capable of self-clearance. Voriconazole was initiated. Despite receiving treatment, her condition showed no improvement over consecutive months. During this period further laboratory tests examined lymphocytes characteristics and revealed a low total T cell count, (ranging from 0.32 to 0.34 × 109 cells/L), low CD8 + T cells (0.065 to 0.087 × 109 cells/L) and low CD4 + T cells (0.26 to 0.28 × 109 cells/L). Further immunophenotyping was conducted on CD4 + T cells, and CD8 + T cells. The patient's B cell count was very low (0.010–0.015 × 109 cells/L), and the CD4 + /CD8 + ratio was elevated to 4.4 due to very low CD8 + cells rather than elevated CD4 + cells. The neutrophil count was normal (5.77–6.34 × 109cells/L).

After seven months, due to persistent symptoms and difficulties in controlling infections in an outpatient setting, the patient was readmitted for one month to initiate treatment for chronic pulmonary aspergillosis (CPA). Voriconazole was switched to micafungin due to a panazole-resistant strain of Aspergillus found in sputum culture. By month 14, significant progression of her lung lesions was observed on the chest CT. Her weight remained low at 33 kg. Treatment for NTM was not possible due to low body weight, and the patient agreed to be admitted on the medical psychiatry unit to improve her nutritional status, initiate NTM treatment, and continue treatment for Aspergillus. Her weight at the time was 32.2 kg, BMI 13.2. One month after intensive refeeding, ethambutol, clofazimine, and azithromycin were started to treat the NTM infection. Amikacin was initiated for two months, and micafungin continued. A screening test for chronic granulomatous disease, in which Aspergillus infections are common, showed a normal oxidative burst of neutrophils and thus normal overall metabolic integrity of phagocytic neutrophils. Further immunological assessment concluded that our patient had no known immunological disorder other than malnutrition that caused immunodeficiency. She was discharged in April 2024; her weight had by that time increased to 40.3 kg, BMI 16.6, and her overall health radically improved. At that time laboratory analysis revealed resolution of leukopenia. Absolute count of lymphocytes, CD3 + T cells and CD4 + T cells rose but remained under reference values. The absolute number of CD8 + T cells and B lymphocytes normalized whereas the NK cell number increased.

Discussion

This report presents two cases of severe opportunistic lung infections with Mycobacterium species and Aspergillus that occurred in patients with immunodeficiency attributable to malnutrition caused by longstanding AN-R including the dynamics of CD8 + T cells, CD4 + T cells, and B cells that corresponded with the fluctuation in body weight.

Changes in peripheral blood cell count are often seen in AN-R which is true for red and white blood cells, as well as platelets [69]. Mild leukocytopenia is common and alterations in T- and B-cells can be found. Bone marrow atrophy and gelatinous transformation (complete atrophy and deposition of amorphous material) are characteristic findings in AN-R and associate with low body fat and may be present half of the patients. These hematological and morphological changes resolve completely and rapidly after refeeding.

Mycobacterium species other than M. tuberculosis and Mycobacterium leprae constitute nontuberculous mycobacteria (NTM), also termed atypical mycobacteria. The predominant causative agent of NTM infections in humans is Mycobacterium avium complex (MAC). The incidence of NTM infections is increasing worldwide in part due to aging [10]. The individuals that are typically at risk to become infected by NTM usually suffer from immune defects or underlying lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease [11]. A retrospective, descriptive study of 182 patients suffering from non-tuberculous mycobacteria (NTM) identified elderly females, particularly those with low BMIs, as a new population at risk for NTM [12]. As expected, a lower BMI appears to independently increase the risk of pulmonary NTM infection [13]. Furthermore, several case reports indicate that malnutrition due to AN may form a risk factor for NTM infections (Table 1).

Table 1 Anorexia and secondary immunodeficiency: cases
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Similarly, A. fumigatus, a common soil-dwelling fungus prevalent in various environments including organic debris, dust, and rotted plants, typically causes no disease in immunocompetent individuals [39]. The clinical presentation of Aspergillus-related infections varies widely, and is largely influenced by the underlying immune status and possible pulmonary disease. This spectrum ranges from acute bronchopulmonary aspergillosis, chronic pulmonary aspergillosis, bronchitis, acute community-acquired, chronic cavitary nodules/aspergilloma to invasive disease in severely immunocompromised individuals [40]. Chronic pulmonary aspergillosis primarily affects individuals with underlying lung conditions like chronic obstructive pulmonary disease, sarcoidosis, or a history of tuberculosis or non-tuberculous mycobacterial disease [41]. Underlying immunosuppression that causes heightened susceptibility to disease caused by Aspergillus is directly proportional to neutrophil dysfunction and reduced number of neutrophils [5]. Of note, our patients did not receive Pneumocystis jirovecii pneumonia prophylaxis, although these infections have been reported in AN-R (Table 1).

Both of our patients experienced opportunistic infections that are typically harmless in healthy individuals but become pathogenic when the body's defense system, e.g. number of B and T lymphocyte, weakens [42]. The most commonly observed and clinically significant immune system abnormalities in patients with AN are a reduced total white blood cell (WBC) count and impaired WBC function [8]. Absolute lymphocyte count is shown to be reduced as observed in both of our patients. Cell-mediated immunity is more affected than humoral immunity in AN-R. T-cell absolute counts are notably reduced [43]. Furthermore, it has been shown that the function of cell-mediated immunity, assessed via the delayed hypersensitivity skin test, is diminished. Additionally, there are alterations in T-lymphocyte subsets [44]. While both CD4 + and CD8 + T cell subtypes are decreased in malnourished children [45], patients with AN are found to present with increased CD4/CD8 T cell ratios due to a more significant reduction in CD8 + T cell counts compared to reduction in CD4 + T cell count [46,47,48]. Our patients showed reduced WBC, reduced total absolute lymphocyte counts, and reduced absolute counts of CD4 + and CD8 + T cells (Fig. 4). An increase in CD4/CD8 T cell ratio was seen in patient 2.

Fig. 4
figure 4

Absolute cell numbers of lymphocyte subsets in two patients: Patient 1 (red dots) and Patient 2 (blue dots), plotted against BMI. The gray areas represent the reference values for each lymphocyte subtype. A positive association between BMI and cell number is observed across all lymphocyte subtypes in both patients

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Several studies have found that total B cell count and relative B cell count in individuals with AN (without infection) are equivalent to those in healthy controls [46, 49]. A more recent study even reported increased total B cell counts, though the percentages remained comparable to those in healthy adolescents [50]. However, in both patients presented in this paper, the B cell count was significantly decreased. Similarly in a study of lymphocyte subsets in malnourished and well-nourished children with bacterial infections, B lymphocytes in malnourished children showed significantly lower values in relation to the results seen with well-fed children [45]. Interestingly, patient 1 displayed a 100-fold increase in total B cell count following refeeding and weight gain. Neutropenia is usually present as well [51, 52]. A study of individuals with anorexia nervosa compared to healthy controls found significant deficit in functions of neutrophils chemotaxis and adherence as well as deficit in granulocyte microbiocidal activity [53]. Lower absolute counts of NK cells are observed in patients with eating disorders, including both restrictive and binge-purge types as supported by both our patients [54].

Malnutrition stands as the primary cause of secondary immunodeficiency globally [55], and it has been linked to immune dysfunction in a variety of settings, including starvation and cachexia in both human beings and animals [56]. There are different mechanisms that may contribute to the AN-R related immune dysfunction. Firstly, immune cells such as lymphocytes rely heavily on glucose uptake [57]. When leukocytes are in a non-activated (resting) state, energy is derived from lipid oxidation and complete oxidation of glucose through the TCA cycle where energy is generated through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. However, during immune activation, leukocytes increase glucose utilization, switching from complete oxidation of glucose to glycolysis and increased pentose phosphate pathway (PPP) flux, which supports cell proliferation by providing necessary glucose-derived products [58]. This shift from oxidative to glycolytic metabolism is critical to maintain T cell function, as decreased glucose availability inhibits T cell cytokine production and proliferation [59]. Several studies have specifically examined the effect of malnutrition on T cell number and function and found decreased T cell numbers fasted mice and in malnourished humans [45, 60]. This suggests that decreased circulating glucose levels during fasting may directly impact T cell metabolism and, consequently, T cell function. Glucose is also vitally used in other immune cells: through the PPP, glucose produces nicotinamide adenine dinucleotide phosphate (NADPH), required by macrophages and neutrophils to generate radicals that kill bacteria and facilitate phagocytosis [58]. In anorexia nervosa (AN), low glucose levels and depleted energy reserves impair glucose availability. In patient 1, absolute counts of lymphocyte subsets normalized shortly after refeeding, although BMI remained in the range of severe AN, which further establishes the importance of available glucose for immune function.

Secondly, neuroendocrine changes may play a role in T and B cell changes. Leptin is an adipokine secreted in proportion to adipocyte mass. In addition to its well-described role in regulating appetite, energy expenditure, and body weight, leptin is also a pro-inflammatory cytokine. Leptin modulates the immune system by promoting T-lymphocyte differentiation, enhancing phagocyte function, and increasing the production of the cytokines TNF-α and IL-12. Moreover, leptin promotes the Th1 immune response by promoting secretion of IFN-γ [61]. In AN-R, levels of leptin are reduced and therefore all the functions above are limited. Leptin-deficient mice have delayed clearance of Mycobacterium abscessus lung infection compared to wild-type mice [62]. Due to its role in stimulating the gonadal axis, reduced leptin secretion is also implicated in decreased estrogen production and the commonly observed amenorrhea in patients with AN-R [63]. Experiments in ovariectomized mice indicate that estrogen enhances the clearance of M. Avium Complex [64], the most common agent causing NTM infection in humans. From data collected from human studies, no definitive conclusions can be drawn [65]. One can speculate that lowered leptin and estrogen levels observed in AN patients could potentially correlate with increased susceptibility to infections, especially to NTM infections.

Additionally in AN, the bone marrow undergoes changes known as gelatinous marrow transformation (GMT) known also as starvation marrow. GMT is characterized by marrow hypoplasia and the interstitial infiltration of a gelatinous substance composed of acidic mucopolysaccharides [66]. GMT is linked to the degree of weight loss in AN, reflecting the patient's nutritional status.

Normally, commensal bacteria in the gut play a crucial role in maintaining immune system health and tolerance through metabolite production, such as butyrate, which supports gastrointestinal epithelial cells. In AN, changes in the microbiota, including decreased production of short chain fatty acids and disruption of the intestinal barrier, can lead to increased activation of the immune system. This dysregulation, coupled with potential decreases in immune tolerance and increased pro-inflammatory cytokine production, may contribute to susceptibility to infections and gastrointestinal disturbances in individuals with AN [67].

Given the heightened risk of infectious complications and reduced febrile response in severe AN patients, early detection methods are imperative [52, 68]. The decrease in lymphocyte subsets (B cells, CD4 + T cells, CD8 + T cells) in patients with AN-R may be one of the indicators of heightened risk for opportunistic infections and complications. Moreover, refeeding and weight gain lead to the normalization or rise of absolute lymphocyte subset numbers.

At this moment, it is difficult to provide pragmatic guidance for what age, fat mass, or hematology lab results should prompt further evaluation of lymphocyte subtypes. However, if these subtypes are analysed and proven to be low, then a high degree of concern for risk of mycobacterial-like infections may be raised. Likewise, the presence of the infections may warrant analysis of lymphocyte subsets which underscores the relevance of periodic clinical assessment. Alternatively, assessment of the lymphocyte count alone may be sufficient. Future studies will need to evaluate if and how lymphocyte subsets can predict the increased risk for opportunistic infections in AN-R.

Data availability

No datasets were generated or analysed during the current study.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Petra Vidmar & Maarten R. Soeters

  2. Department of Respiratory Medicine, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Josje Altenburg

  3. Department of Laboratory Medicine, Laboratory Specialized Diagnostics and Research, Section Medical Immunology, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Ester M. van Leeuwen

  4. Department of Social Pediatrics, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Annemarie C. M. van Bellegem

  5. Department of Psychiatry, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Chantal Verhoef

  6. Department of Infectious Diseases, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands

    Godelieve J. de Bree

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Contributions

PV MRS wrote the main manuscript text PV prepared figures EMvL performed lab work on blood cells MRS, CV, JA, ACMvB and GJdB performed clinical tasks on the patients All authors reviewed the manuscript.

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Correspondence to Maarten R. Soeters.

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Vidmar, P., Altenburg, J., van Leeuwen, E.M. et al. Lymphocyte subsets and the increased risk for opportunistic infections in severe restrictive anorexia nervosa. J Eat Disord 13, 84 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40337-025-01235-9

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40337-025-01235-9

Keywords

Journal of Eating Disorders

ISSN: 2050-2974