While some studies have reported that AN represents an immunocompromised state, others describe the immune system of patients with AN as dysfunctional or simply altered.9,11,22,28 Some studies have found that patients with AN had delayed reactions to pathogen skin exposures compared with healthy controls, which provides evidence of an impaired cell-mediated immune system.9,27,29
Some studies have considered the consequences of infection and immunologic findings as markers of or contributing to the onset of AN.2,30,31 Numerous studies have noted abnormalities in AN with regards to cell-mediated immunity, the humoral system, the lymphoreticular system, and the innate immune system, and potential contributions from increased oxidative stress, a chronically activated sympathetic nervous system and hypothalamic-pituitary-adrenal axis, altered intestinal microbiota, and an abnormal bone marrow microenvironment.2
Box 1
The immunology of COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta-coronavirus that is still being studied for its effects on the immune system. It may take years to fully understand the nature of the pathogen and the response of the human immune system. To better understand COVID19, researchers have been turning to what they learned from the past outbreaks of severe acute respiratory syndrome (SARS) in 2003- 2004 and Middle East respiratory syndrome (MERS) in 2011, both caused by betacoronaviruses with a zoonotic origin.25,32
The proposed pathogenesis for infection of SARS-CoV-2 is similar to SARS and occurs when aerosolized droplets containing the virus enter the host.32 While currently there is only initial data on the host innate immune status of patients infected with SARS-CoV-2, initial findings of a report on 99 cases in Wuhan, China included increased total neutrophils (38%), reduced total lymphocytes (35%), increased serum interleukin-6 (52%), and increased C-reactive protein (84%).33 Additional findings were decreased percentages of monocytes, eosinophils, and basophils, as well as significantly decreased levels of cytokines and T-cells in more severe cases.19 Past research with SARS reported similar T-cell findings, with a more frequent CD8+ response and a greater magnitude of CD4+.34
Box 119,25,32-34 describes some of the initial immunologic findings reported in patients with COVID-19. In Box 2,5,8,11,13,14,19,26,28,35-40 we discuss reports that describe the immunologic overlay of COVID-19 and AN.
Box 2
The immunologic overlay of COVID-19 and anorexia nervosa
Leukopenia (low leukocyte levels) is a common finding in patients with anorexia nervosa (AN),8 and often leads clinicians to lower their suspicion for infection. A 2008 Hungarian study that evaluated lymphocyte activation parameters and clinical status in 11 adolescents (10 girls and 1 boy) with AN, 12 obese adolescents, and 10 healthy controls did not find any association between the variables.35 While many studies have focused on adults, it is important to note that leukopenia is a common finding in adolescents (age 12 to 17) with AN.36
Leukocyte counts are elevated in coronavirus disease 2019 (COVID-19), possibly offsetting AN’s leukopenia. In addition, neutrophil counts are elevated and monocyte, eosinophil, basophil, and especially lymphocyte counts are significantly decreased. A meta-analysis that included 22 studies and 924 participants (512 with AN and 412 controls) examined common inflammatory cytokine findings in patients with AN.11 Compared with healthy controls, patients with AN had significantly elevated levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, IL-6, and TNF-receptor II, and significantly decreased levels of C-reactive protein and IL-6 receptor. Elevated levels of TNF-alpha and IL-6 also have been reported in patients with COVID-19.19 These findings may mask suspicion for infection in patients with AN.19
In patients with AN and those with bulimia nervosa, CD4+-to-CD8+ ratios also have been found to be low as a result of normal-tohigher levels of CD4+ cells and lower levels of CD8+ cells.36-39 Researchers have also proposed that the lymphocytosis observed in AN is a result of increased naïve CD4+.36 In AN, total lymphocyte counts have been found to correlate positively with a patient’s body mass index (BMI), while the CD4+ T-lymphocyte correlated negatively with BMI and were critically low in patients with severe malnutrition.26,40 In patients with COVID-19, CD4+ levels have reported to be within normal range, naïve CD4+ cells were elevated, and CD8+ cells were slightly decreased,19 which is similar to the findings in AN.
Fewer studies have evaluated humoral immune response in AN, and results have varied. One study (N = 46) found elevated B-cell counts in adolescents with AN-restricting type,36 while another (N = 40) reported normal levels of B-cells.5 Specific decreases in immunoglobulin (Ig) G and IgM have also been reported in AN, while IgA, IgG, and IgM usually are normal in COVID-19.19
Despite differences in immune system function, cellular immunity appears to remain relatively intact in patients with AN, but can become compromised with severe malnutrition or with advanced weight loss.28,40 This compromised immunity related to severe AN with a very low BMI likely leads to the increased morbidity and mortality.8,13,14
Malnutrition and the immune system
Differences in the type of malnutrition observed in low-weight patients with AN may help explain why patients with AN can maintain a relatively intact cell-mediated immune system.1 Protein-energy malnutrition (PEM), which is found in typical states of starvation, consists of deficiencies in multiple vitamins, protein, and energy (caloric content), whereas the dietary habits of patients with AN usually result in a deficiency of carbohydrates and fats.41 Studies that examined the impact of PEM on immunity to influenza infection have suggested that balanced protein energy replenishment may be a strategy for boosting immunity against influenza viral infections.42 However, carbohydrates are the primary nutrients for human bone marrow fat cells, which play a crucial role in the maturation of white blood cells. This may account for the leukopenia that is common in patients with AN.6,43 The protein-sparing aspect of the typical AN diet may account for the immune system changes observed in patients with AN.44
Although some studies have proposed that immune deficiencies observed in patients with AN are secondary to malnutrition and return to normal with refeeding,5,40,45 others have concluded that immune function is not compromised by factors such as nutritional status or body weight in AN.26,43,46
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