ICL is a rare condition that is found worldwide, with unknown incidence and etiology, and it is viewed as a syndrome that likely encompasses different disorders caused by the reduction of CD4 cell numbers. CD4 is a glycoprotein expressed on the surface of various types of helper and regulatory T cells. CD4 + T cell is an important immune cell that regulates the activities of cells participating in immune responses, participate in apoptosis (programmed cell death), and tumor monitoring. Patients with ICL will develop opportunistic infections, malignancies, and/or autoimmune diseases . Cryptococcal meningitis is the most common opportunistic infection. According to a series of studies, one-third of patients were infected with cryptococcus, while around 10% were infected with the varicella-zoster virus . Cryptococcus was reported to be the most frequent infection in 258 ICL patients (26.6%), followed by mycobacterial (17.0%), candidal (16.2%), and varicella-zoster virus infections (13.1%) .
CD4 + T cells should be assessed when the patient presents with unusual or recurrent infections. However, the infection can be associated with lymphocyte changes, and it is impossible to determine whether changes reflect a primary immunologic defect or the response to infection. Our patient suffered disseminated cryptococcal infection and herpes virus infection with no underlying disease and HIV or tuberculosis, but a series of low CD4 + T cells lasting for more than 3 months. As reported, anti-cytokine autoantibodies have also been related to opportunistic infections, with anti-IFNγ autoantibodies linked to disseminated nontuberculous mycobacterial infections and anti-IL-17 autoantibodies linked to chronic mucocutaneous candidiasis, and anti-IL-6 autoantibodies linked to Staphylococcal infections . Anti-GM-CSF autoantibodies have also been found in a few cryptococcal meningitis patients caused by Cryptococcus. Gattii, but not Cryptococcus. neoformans [10, 11]. However, CD4 + T cells were normal or slightly lower in most patients .
Cryptococcal meningitis is not uncommon in the clinic, and ICL remained poorly understood to clinicians. There are few systematic reviews on ICL and cryptococcal meningitis. A systematic search was performed on PubMed between 1992 and December 2020. A combination of the following search terms was used: cryptococcosis, cryptococcus infection, cryptococcal meningitis, idiopathic CD4 lymphocytopenia, ICL, HIV negative CD4 lymphocytopenia. 26 cases were enrolled for analysis [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Among those patients, 20 (76.9%) were male, 6 (23.1%) were female. The median age was 42 (range 4.5–75) at diagnosis. Cryptococcosis in ICL patients usually had a subacute or chronic course and took weeks to months from symptom until diagnosis . The most common symptoms were headache, fever, nausea/vomiting, and meningeal irritation. The symptoms in those 26 patients were described in Table 2. The primary symptoms were headache and fever (73.1%, 61.5%). Nausea, vomiting, and disorientation were also common. The patients suffered only headaches at the early period. Therefore, some patients might have atypical manifestations during the process of disease.
Cerebrospinal fluid were analysed in 22 cases with adequate information in Table 3 [13,14,15,16,17,18,19, 21,22,23,24, 26, 27, 29, 31,32,33,34,35,36]. It showed a median leukocyte of 61 cells/μL (ranging 0–700), mainly constituted by lymphocytic, glucose of 39.1 mg/dL (ranging 1.98–87 mg/dL), below 40 mg/dL (1 mM/L = 18 mg/dL) in 50% of the patients, and protein of 116 mg/dL (ranging 20–266 mg/dL). The India ink stain and cryptococcal antigen titer positive rates were 12/14 (86%) and 15/16 (94%), respectively. The positive rate of CSF culture was 18 /19 (95%), Only one case was Cryptococcus. gattii and all the others were Cryptococcus neoformans. Cryptococcal meningitis is linked to a high rate of morbidity and death. Poor outcomes have previously been linked to advanced age (≥ 60 years), solid malignancy, hematologic malignancy, liver cirrhosis, respiratory failure, long-term ICU stay, corticosteroid treatment, and disturbed mental state (coma, seizure, herniation) [38,39,40,41]. Low CSF leukocyte counts (less than 20 cells/microL), low CSF glucose, high CSF CrAg titers (> 1:1024), high CSF opening pressure (≥ 250 mm H2O), lower Glasgow Coma Scale (GCS) scores, hematogenous dissemination of cryptococcosis, hydrocephalus, and cerebral infarction have all been linked to poor outcomes [38, 40,41,42,43,44,45,46].
Cryptococcal infection and ICL have an increased likelihood of developing dermatomal zoster . However, due to a lack of systems analysis, it is not sure whether this coinfection can be more severe than a single infection. We consider the deterioration of our patient is related to the activation of the varicella-zoster virus. We believe it may also require more cases or literature reviews.