Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient

Introduction

Toxoplasma gondii is an obligate intracellular protozoan with a wide host range among vertebrates, including humans¹. Domestic cats and their relatives, the definitive hosts of T. gondii, release large numbers of unsporulated oocysts in their feces, which are then ingested by secondary hosts. Major sources of infection include ingestion of contaminated water or undercooked meat and exposure to other materials contaminated with cat feces, although transmission can also occur by transplantation, blood transfusion and laboratory accidents. Human infection has been estimated to occur in ~30% of individuals worldwide based on seroprevalence studies but usually results in lifelong subclinical infection in immunocompetent individuals. Chronic infection most commonly manifests as tissue cysts in skeletal muscle, myocardium, brain and eye. Acute toxoplasmosis in immunocompetent individuals may present as a mononucleosis-like syndrome. In the setting of acquired immunodeficiency, toxoplasmosis may occur as a result of primary T. gondii acquisition or reactivation of latent infection and may present as systemic illness or as a localized infection. Central nervous system toxoplasmosis is a particular problem in AIDS patients and is an AIDS-defining condition. Ocular toxoplasmosis can also occur in AIDS patients and may even be the presenting manifestation². Vertical transmission of T. gondii is ~40% for women who become infected during pregnancy and may cause severe congenital developmental defects involving the brain, eye and other organs. In the eye, T. gondii may cause a progressive and recurring necrotizing retinochoroiditis and is the most common cause of infectious uveitis worldwide. Optic neuritis is a less frequent presentation that is usually associated with worse visual outcome. Ocular toxoplasmosis occurs in patients with acquired immunodeficiency but has not previously been reported in patients with primary immunodeficiency disorders.

Warts-Hypogammaglobulinemia-Infections-Myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4³. The primary manifestations of WHIM syndrome are cutaneous and mucosal warts, hypogammaglobulinemia, recurrent non-invasive infections, which are usually bacterial in origin and typically affect the oto-sino-pulmonary tract and skin, and myelokathexis, a term coined for retention of mature neutrophils in bone marrow. Opportunistic and life-threatening infections in WHIM syndrome patients are rare, and significant protozoan infection has not been previously reported.

Clinical course and management

Diagnosis

The patient appeared well-developed but underweight (BMI = 14.5) with mild scoliosis. Splenomegaly was noted. Classic features of WHIM syndrome were present, including cutaneous warts, hypogammaglobulinemia, and severe panleukopenia (Table 1). A bone marrow biopsy revealed myelokathexis with an elevated 4:1 myeloid:erythroid ratio. In the right eye, light perception was absent and there was an afferent pupillary defect. Dilated fundus examination showed a pale retina with widespread white subretinal infiltrates with a necrotizing appearance in some areas, patches of subretinal fibrosis, mild vitritis and a fibrotic band reaching the optical nerve head and a pale optic nerve (Figure 1). Spectral domain optical coherence tomography images showed variable hyper-reflective infiltration of the subretinal space throughout the macula without serous subretinal fluid, with disruption of normal lamination of the macula. B-scan ultrasound showed mild vitreous opacities with presence of a posterior hyaloid membrane still adherent to the optic disc, but separated from the retina in other areas posteriorly, with presence of a vitreoschisis cavity inferiorly, without any retinal detachment, and without any definite eye wall thickening or episcleral lucency. The left eye was normal. Cranial CT scan showed mild sinusitis. Filgrastim (1 mcg/kg/day) was given resulting in increased ANC and increased vitritis the next day, suggesting the possibility of an ongoing chronic infection. Peripheral blood cultures were negative. A vitreous biopsy showed mixed inflammatory cells, and PCR testing was positive for T. gondii in vitreous fluid but negative in serum and bone marrow. Serum IgG for T. gondii was 599 international units/ml. Tests for other viral (CMV, EBV, VZV, HSV, dengue), fungal (Histoplasma, Cryptococcus), bacterial (Bartonella, Rickettsia, Legionella, Mycobacterium) and parasitic (Leishmania, Toxocara) pathogens were negative. A diagnosis of advanced ocular toxoplasmosis with ongoing active lesions was made.

Table 1. Hematologic characteristics of the patient upon presentation to NIH.

WBC: white blood cells; RBC: red blood cells; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; AMC: absolute monocyte count; NK: natural killer cells. Measured values for the cell counts are cells/µL, except as otherwise noted; values outside of the normal reference range are bolded.

Characteristic	Value	Reference range
WBC	1060	4230–9010
RBC	5.04 × 106	4.62–6.08 × 106
Hematocrit (%)	39.9	40.1–51%
Hemoglobin (g/dL)	13.4	13.7–17.5
Platelets	1.4 × 105	1.61–3.47 × 105
ANC	130	1780–5380
ALC	880	1320–3570
AMC	40	30–820
Eosinophils	10	40–540
Basophils	10	10–80
NK	213	126–729
NK-T	59	29–299
CD3+	663	714–2266
CD4+	259	359–1565
CD4/CD45RA+	4	102–1041
CD8+	338	178–853
CD8/CD45RA+	10	85–568
CD20+	6	59–329
IgG (mg/dL)	724	716–1711
IgM (mg/dL)	98	15–188
IgA (mg/dL)	9	47–249
IgE (IU/mL)	24.2	0–90

Figure 1. Shown on top are montage fundoscopic images of the patient’s right (OD) and left (OS) eyes at the time of presentation.

The lower right panel shows the optical coherence tomography findings at presentation for OD (top) and OS (bottom).

Discussion

To our knowledge, this is the first detailed report of localized ocular toxoplasmosis in a primary immunodeficiency disorder and the first report of a protozoan infection in WHIM syndrome. In addition, optic nerve involvement as seen in our patient is rare in ocular toxoplasmosis (<5%)⁴.

Although symptomatic toxoplasmosis occurs frequently in the setting of acquired immunodeficiency, especially HIV infection, it is rarely associated with a primary immunodeficiency disorder. Disseminated toxoplasmosis has been reported in several patients with X-linked hyper-IgM (XLHI) syndrome^5–9. Neutropenia was observed in two of these patients^5,7. Two patients were receiving IVIg replacement therapy at the time toxoplasmosis was diagnosed,^5,8 while two others were previously undiagnosed with XLHI and had untreated hypogammaglobulinemia^7,9. Of note, one patient had been taking trimethoprim/sulfamethoxazole as prophylaxis for recurrent otitis media prior to the onset of symptomatic toxoplasmosis⁵. Disseminated T. gondii infection with ocular manifestations has been reported in a patient with ataxia telangiectasia¹⁰. This patient did not have lymphopenia and had received IVIg replacement therapy. In addition, fatal cerebral toxoplasmosis was reported in two patients with common variable immunodeficiency^11,12.

Thus, hypogammaglobulinemia is a common feature of primary immunodeficiency disorders in which toxoplasmosis has been reported, suggesting the importance of antibody-mediated immunity for controlling T. gondii. Although our patient had a total IgG level just above the lower limit of normal, he developed a strong specific IgG response to T. gondii. The quality of the antibodies and the kinetics of the response are unknown but evidently were insufficient to initially control the pathogen. Cell-mediated immunity is also important in control of T. gondii infection, with critical complementary roles for monocytes, neutrophils, dendritic cells, plasma cells, and CD4+ and CD8+ T cells¹³. IFNγ and IL-12 are hallmarks of the Th1 response to T. gondii infection¹³. Neutrophils, activated monocytes, macrophages, and dendritic cells all produce IL-12, whereas IFNγ is produced by NK cells, neutrophils, and effector T cells in response to T. gondii invasion¹³. In limited studies, mature DCs from WHIM patients have been reported to produce normal amounts of interleukin-12 (p70) and IFN-γ production has been reported to be similar between CD4⁺ T cells from a healthy donor and a WHIM patient activated by anti-CD3– and anti-CD28–coated beads^14,15.

An explanation for the paucity of symptomatic T. gondii infections among patients with primary immunodeficiency is lacking. Possible explanations include the frequent use of broad-spectrum antibiotics such as trimethoprim-sulfamethoxazole for patients with primary and acquired immunodeficiency disorders and environmental precautions taken to limit exposure to pathogens in general.

WHIM syndrome is a complex, phenotypically heterogenous primary immunodeficiency disorder that frequently involves defects in steady state levels of leukocytes and antibody in the blood, as in our patient. Given that the patient has multiple immunologic abnormalities, it is not possible to attribute his susceptibility to T. gondii to any single one. A previous study has detailed a role for CXCR4 in regulating Plasmodium development in mouse and human hepatocytes, but no animal studies have been published to date that evaluate CXCR4 signaling in T. gondii or other protozoan infections¹⁶.

In summary, we describe in detail a very rare case of primary ocular toxoplasmosis in primary immunodeficiency disease and the first case of protozoan infection in WHIM syndrome. The precise immunologic abnormalities among the spectrum of abnormalities resulting from WHIM syndrome that predisposed the patient to such a devastating outcome of T. gondii infection are currently unknown.

Consent

Written informed pediatric assent was obtained from the patient, and the patient’s mother provided parental written informed consent for the publication of the patient’s clinical details and any associated images.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.