Clinical presentation of idiopathic CD4 lymphocytopenia

Abstract

An otherwise healthy man (60s) presented to our emergency department 5 years ago with stroke-like symptoms. Underlying cryptococcal meningitis infection was ultimately discovered leading to extensive workup to rule out underlying malignancy and HIV infection. Results returned negative with the exception of a CD4 count less than 25 /mm³. Several years later, he again presented to the emergency department with fatigue. He was then found to have severe anaemia with underlying Mycobacterium avium complex (MAC) infection involving the bone marrow and a left psoas abscess. After multiple courses of antibiotic therapy targeted towards MAC, the infection persisted due to bone marrow involvement. By diagnosis of exclusion, he was eventually found to have idiopathic CD4 lymphocytopenia. Here we describe this condition, which has the potential to cause significant morbidity, and obligates the need for high clinical suspicion for timely diagnosis to enhance life quality and outcomes for patients.

Background

Idiopathic CD4 lymphocytopenia (ICL) is an exceedingly rare and difficult disease to detect and manage. The first case was identified 30 years ago and currently, literature has been mostly limited to case reports. Typically, patients will present with opportunistic infections that are commonly associated with HIV/AIDS, such as the patient in this report. As a result, ruling out HIV rule is one of the core criteria for diagnosing ICL. The criteria include: (1) CD4 count <300 cells/mL or <20% of total lymphocytes taken at two points at least 6 weeks apart, (2) HIV serology is negative and (3) therapy induction of diminished CD4 or other causes of immunodeficiency are not present.¹ Epidemiologically, patients most often present in the fourth decade of life, most commonly with an opportunistic infection.¹ It is not well documented how prevalent this disease is in the general population.

Case presentation

An otherwise healthy man in his 60s initially presented to the emergency department 5 years prior to our encounter with stroke-like symptoms with acute onset of left upper and lower extremity weakness. At that time, neuroimaging was completed, and he was found to have an area of increased density on CT scan of the brain suspicious for ischaemic cerebrovascular accident (CVA). As part of his evaluation, a lumbar puncture was performed, revealing a diagnosis of cryptococcal meningitis that was then presumed to be the likely culprit of his stroke. Given the unusual nature of the infection, serology for HIV was completed that subsequently returned negative. Further analysis into possible malignancy yielded negative results as well. He was treated for the infection and recovered fully without a definitive underlying cause for it established. Also, during this time, he was incidentally found to have an asymptomatic psoas abscess on abdominal imaging as well. At that time, the abscess was not aspirated due to difficultly in accessibility and relatively small size.

He returned to the hospital 5 years later with weakness, fatigue and malaise. Initial labs were drawn, and he was found to have a haemoglobin/haematocrit of 80 g/L/24.9%. He was admitted to the hospital for symptomatic anaemia and transfusion with two units of packed red blood cells was administered. Resolution of his symptoms occurred following this treatment. Within the past several months, he was admitted multiple times with recurrent symptomatic anaemia. Each time, the workup for possible underlying malignancy or chronic disease was negative. Subsequently, an extensive workup was done with laboratory results significant for pancytopenia and a CD4 count of <25/mm³, which prompted a bone marrow aspirate to be performed. Mycobacterium avium complex (MAC) infection of the bone marrow was discovered at that time. Repeat HIV testing resulted in negative findings and there was no identifiable cause of this lymphocytopenia. Due to his negative HIV results, bone marrow biopsy results, and complex medical history, a diagnosis of ICL was concluded.

During the patient’s hospital stay, the left psoas area (figures 1 and 2) with the abscess was reassessed by an infectious disease specialist and general surgeon, both of which had previously been involved in the patient’s care for his cryptococcal meningitis and left psoas haematoma drainage, respectively. The patient underwent an aspirate of the psoas fluid collection for culture, but interventional radiology was unable to access any of the fluid (figure 3). The fluid was too gelatinous to be aspirated, and general surgery found the location to be difficult to resect and drain. No culture has yet to be obtained on this abscess. The patient was discharged on hospital day 4 back to his skilled nursing facility with continued treatment for his MAC infection. It is not certain if his psoas fluid collection was present before or after this patient developed ICL; however, it was persistent during his course of treatment and posed symptomatic issues for him as it persisted.

Figure 1.

CT scan of abdomen and pelvis with oral contrast. Axial view of psoas abscess at the level of the mid-kidney.

Figure 2.

CT scan of abdomen and pelvis with oral contrast. Coronal view of the left psoas abscess displacing the kidney. Hepatosplenomegaly may also be appreciated from this angle.

Figure 3.

CT-guided cyst aspiration of the left psoas abscess. Posterior approach taken by interventional radiology in an attempt to relieve the patient of this abscess.

Investigations

Investigations for this patient included complete blood counts (CBCs), CT scans and cytology. HIV PCR tests were conducted multiple times as well. After multiple negative results, bone marrow aspirations were obtained during his visit 5 years prior, as well as his most recent visit. As discussed throughout the case and discussion, the patient presented with MAC infection that had disseminated to the bones. This was diagnosed on culture of bone marrow aspirate, at which time the patient’s CD4 count was obtained. This is the gold standard for bone marrow infection diagnosis, and CD4 count is a requirement for the diagnosis of ICL. Serial CT scans were done to assess the presence of a left psoas muscle abscess that was attempted to be aspirated but was never successfully excised or cultured due to location and consistency of the fluid collection. Medical history included stroke caused by cryptococcal meningitis which was diagnosed by MRI at that time. Further explanation of CT scans can be seen in Figures 1-3.

Differential diagnosis

The immediate diagnostic dilemma was the patient’s initial presentation with cryptococcal meningitis. This is an illness typically seen in advanced AIDS. On serology testing, the patient was found to be negative for both HIV-1 and HIV-2 and was then subjected to bone marrow aspiration. At that time, he was found to have a CD4 count that was under 25 /mm³. This was the result of a single aspiration, however, and was, thus, not sufficient to lead to a diagnosis of ICL. Moreover, ICL is a diagnosis of exclusion, therefore further workup must be done to exclude other diseases. Malignancy was another potential cause for this patient’s presentation, and thus, he had complete blood workup, including CBC and complete metabolic panel (CMP), along with MRI brain, echocardiogram and CT abdomen/pelvis. These all returned negative, except for the CVA that was diagnosed on his initial arrival at the emergency room.

On the patient’s subsequent hospitalisation for symptomatic anaemia, he was once again evaluated with a thorough workup to find a possible cause for his anaemia. Upper and lower endoscopy was done to rule out gastrointestinal bleed, as well as HIV, again. The bleed, as well as HIV, again. The bleed, as well as HIV, again. The patient had negative serologies for both HIV-1 and HIV-2 on repeat examination. After a second bone marrow aspiration, he was again found to have CD4 count below 25 /mm³. A repeat workup for malignancy returned negative, the patient had two separate measurements of CD4 below 300 /mm³, negative HIV serology and no other likely cause of this lymphocytopenia; he was given the diagnosis of ICL.

Treatment

The patient was discharged on day 4 of his stay with clarithromycin, moxifloxacin, trimethoprim–sulfamethoxazole, rifabutin and amikacin targeting the MAC infection in the bone marrow. He returned shortly thereafter with another episode of symptomatic anaemia, making it the fifth hospitalisation in the past 2 ½ months.

ICL is an especially rare disease that is marked by decreased CD4 counts and no other likely sources of autoimmune disease. The disease most commonly presents in the fourth decade of life, usually with an opportunistic infection. The pathophysiology is unknown due to the rarity of the disease, but could be caused by deficiencies in interleukins, increased apoptosis, or due to yet identified genetic causes. Because the disease presents similarly to late-stage HIV infection, most management has been influenced by similar treatment, including prophylactic antibiotic use. New research is being conducted on the role interleukin therapy could play in the management of these patients. The most critical period of monitoring should be the 3 years following the initial presentation of the patient, as this is the most common period to see a new opportunistic infection in patients with ICL.

Outcome and follow-up

His psoas abscess had grown, leading to a fistula and a superficial lesion on his lower back. This lesion was subsequently incised and drained, but the psoas abscess remains due to limitation of treatment options for him. The patient continues to live with his MAC infection several months after his initial diagnosis, emphasising the devastation that ICL causes for patients.

Discussion

While it is unknown what causes ICL, there are several hypotheses that have been proposed. One such hypothesis is an upregulation of the Fas ligand, causing an increased rate of apoptosis of CD4 cells, and, thus, a decreased overall CD4 count.¹ Another hypothesis that has come to the forefront is a lack of interleukin-7 (IL-7) protein. These proteins are important for stimulation of the Janus Kinase/signal transducers and activators of transcription (JAK–STAT) pathway which causes cell cycle progression.¹ Additionally, the protein is crucial for survival and production of T cells. In patients with ICL, the CD127 receptor, what IL-7 binds to, was shown to have lower expression and decreased responsiveness to the presence of IL-7.¹ Naturally, the body responds by increasing the amount of IL-7, but in patients with ICL, this is not sufficient to enhance the CD4 levels to an appropriate amount.¹ Other hypotheses are in the areas of genetic abnormalities, immune senescence and CD4 sequestration.¹

Because the disease is so rare and the causes are not fully understood, development of therapies is limited. The current mainstay of treatment includes an approach similar to that of HIV.² Patients may be given prophylactic antibiotics to combat broad categories of bacterial organisms seen in treatment of patients with advanced-stage HIV.² Patients are also encouraged to have labs drawn every 4 months to monitor CD4 levels and trends. It is currently recommended that patients are most closely monitored during the first 3 years of their diagnosis, as this has been shown to be the most common period for the development serious systemic infections in ICL.² Other treatments have included intravenous immunoglobulin (IVIG) infusions in patients affected by warts secondary to papilloma, tuberculosis (TB or invasive herpes were of concern as well.³ For now, treatment is geared towards symptom management and addressing the underlying bacterial organisms with which most patients initially present.³

Advancements in therapy are being made currently, however. There have been recent experimental trials done on patients with ICL in 2016. The investigation aimed towards the administration of IL-7.⁴ As discussed earlier, this is one of the proposed mechanisms by which the disease may develop. During these trials, 21 patients with ICL were enrolled, 9 of which were given rhIL-7, the recombinant human form of IL-7 used through injections.⁴ The nine patients were split into groups of three, with each patient in the group receiving a dose of 3 µg/kg, 10 µg/kg or 20 µg/kg.⁴ After a 1-year follow-up, the study demonstrated T cell expansion in peripheral blood and tissues and was safe for use in patients with ICL.⁴ An important note is that patients with poorly controlled opportunistic infections were excluded from the experiments in this trial; meaning, there were no gravely ill patients in these trials.⁴

For our patient, he had a severe MAC infection that occupied space in the bone marrow and caused frequent symptomatic anaemia. Furthermore, he had a concomitant psoas muscle abscess that was a source of bacterial growth. Historically, such abscesses would be treated with incision and drainage. However, recent research has suggested that management medically with targeted antibiotic therapy has been most effective in patients with psoas abscesses.⁵ Most psoas abscesses have been associated with Mycobacterium tuberculosis, followed by Klebsiella pneumoniae species.⁶ Therefore, most antibiotic treatments should be geared towards atypical coverage. The placement of our patient’s psoas abscess made it difficult for a percutaneous approach to drain the abscess and his immunocompromised status also disqualified him for surgical intervention. As a result, treated non-surgically for the abscess with his treatment focused on resolving the MAC infection first.

The literature on ICL is scarce. The first case series was published in 1992, describing five patients who were all discovered to have AIDS-defining illnesses.⁷ This was unique in the fact that these patients had life-threatening systemic infections, whereas there had been cases of Kaposi sarcoma found in patients with normal immune function.⁷ The only concerning finding in these patients were decreased CD4 counts, in the setting of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia and disseminated eczema herpeticum in one patient.⁷ Further PubMed literature review found eight similar case reports of Mycobacterium being discovered in patients with ICL, but there was only one other case of Mycobacterium spp being the presenting illness. In that case, the patient was an elderly (80s) woman who had presented to clinic with several cutaneous nodules, which were later discovered to be Mycobacterium intracellulare.⁸ Unlike our patient, this patient had cutaneous manifestations as opposed to spread to bone marrow.⁸ Interestingly, however, that patient had intra-abdominal abscesses, located in the liver, instead of the psoas muscle as our case.⁸ This may be a connection that warrants further examination as more cases similar to ours arise.

Learning points.

• Idiopathic CD4 lymphocytopenia is a diagnosis of exclusion. Autoimmune diseases/disorders and malignancies must be ruled out to begin suspecting this diagnosis.

• Many illnesses commonly seen in advanced immunodeficiency states such as AIDS can present in this patient population and require a full workup.

• There is no known cause or cure for this pathology. Current treatment regimens are geared towards treating the underlying infection.

• Patients should be discharged with close follow-up by an infectious disease expert.

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