Screening for Humoral Immunodeficiency in Patients with Community-Acquired Pneumonia

DISCUSSION

In our study, the prevalence of low Ig levels in CAP was 38%, with IgG hypogammaglobinemia being the most common class of hypogammaglobinemia. This rate is slightly higher than that found in a previous work by de la Torri et al.,²¹ who reported a prevalence of 28.9% in the inpatient population. The lower prevalence in the de la Torri et al. study was likely secondary to the exclusion of patients who did not have recorded Ig levels.²¹ Additionally, de la Torri et al. noted an inverse relationship between serum IgG levels and CURB-65. These results were not replicated in our analysis. This is likely due to the relatively low number of patients in each category of CURB-65 score in our study focusing only on inpatients. However, low IgG levels were associated with increased length of stay (5 days, IQ range [3-10] vs 3 days, IQ range [2-5]).

Sepsis can cause hypogammaglobinemia.^22,23 The mechanism behind this phenomenon remain unclear, but several theories have been proposed. Sepsis results in endothelial dysfunction, vascular leakage, lymphopenia, and quantitative and qualitative defects in T and B cells.²³ This potentially leads to impaired production and increased catabolism of immunoglobulins. Immunoglobulins play an essential role in recovery from sepsis, and there may be increased consumption during acute illness.^24-28 Regardless of the mechanism, hypogammaglobinemia with SIRS, sepsis, and septic shock has been shown to be a risk factor for increased mortality in these patients.^22,23 There is currently no consensus on the optimal time to screen for humoral immunodeficiency or evaluate the immune system after infection, such as CAP. Some would argue that Ig levels are lower during an active illness and, therefore, this may not be an appropriate time to evaluate Ig levels. However, we believe that inpatient hospitalization for CAP provides a window of opportunity to selectively screen these patients at higher risk for PIDD for underlying immune defects. A hospital-based approach as demonstrated in this study may be more productive than relying on an outpatient evaluation, which often may not occur due to patient recall and/or fragmentation of care, thus leading to the well-recognized delay in diagnosis of immunodeficiency.^5,6In our study, one patient was diagnosed with multiple myeloma, three were diagnosed with specific antibody deficiency, and one was diagnosed with selective IgA deficiency. The patient with multiple myeloma was a 79-year old male who presented with his first ever episode of CAP, along with modest anemia and a creatinine of 1.6. His only other infectious history included an episode of sinusitis and one episode of pharyngitis. Additional evaluation included serum and urine electrophoresis, followed by bone marrow biopsy. This patient’s multiple myeloma diagnoses may have been missed if Ig levels had not been evaluated. Three patients were diagnosed with specific antibody deficiency. All these patients were above 50 years of age; two out of the three patients in this group had experienced a previous episode of pneumonia, and one had a history of recurrent sinusitis. Lastly, one patient was diagnosed with selective IgA deficiency as defined by undetectable IgA in the setting of normal IgG and IgM. This 56-year-old patient had a history of multiple episodes of sinusitis and three previous episodes of pneumonia, one requiring inpatient hospitalization. Earlier diagnosis of patients with specific antibody deficiency and selective IgA deficiency can guide management, which focuses on appropriate vaccination, the use of prophylactic antibiotics, and the possible role of Ig replacement in patients with specific antibody deficiency.

Of the 100 patients who underwent screening for immunodeficiency in the setting of CAP, five were found to have clinically significant humoral immunodeficiency, resulting in a number needed to screen of 20 to detect a clinically meaningful immunodeficiency in the setting of CAP. The number needed to screen by colonoscopy to detect one large bowel neoplasm in patients >50 years of age is 23.²⁹ The number needed to screen to diagnose one occult cancer after an unprovoked DVT is 91.³⁰ Based on this information, we feel that future, larger studies are required to evaluate the utility and cost-effectiveness of routine Ig screening for CAP requiring inpatient hospital admission.

We acknowledge limitations to this study. First, this study only evaluated adults in the inpatient floor setting, and therefore the results cannot be applied to the pediatric population or patients in the outpatient or ICU setting. Second, rather than completing a follow-up evaluation in all patients with abnormal immunoglobulins, we selected patients for additional evaluation based on criteria predefined by an immunologist. Although our rationale was to minimize additional diagnostic testing in individuals with mild hypogammaglobinemia, we acknowledge that this could have led to missing subtler humoral defects, such as a patient with near-normal Ig levels but a suboptimal response to vaccination. Third, due to the design of the study, we did not have a healthy matched control group. Despite these limitations, we believe our results are clinically meaningful and warrant future, larger scale investigation.

In conclusion, there is a high prevalence of hypogammaglobinemia in patients admitted with the diagnosis of CAP. IgG hypogammaglobinemia is the most commonly decreased class of Ig, and hospital length of stay is significantly longer in patients with low levels of IgG during admission for CAP. Additional immune evaluation of patients with CAP and abnormal Ig levels may also result in the identification of underlying antibody deficiency or immunoproliferative disorders.