Tubulointerstitial nephritis and uveitis syndrome following meningitis and systemic lymphadenopathy with persistent Toxoplasma immunoglobulin M: a case report

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal multisystemic autoimmune disease that may occur in response to various environmental triggers, including drugs and microbial pathogens [1]. Since TINU syndrome was first described by Dobrin in 1975 [2], only about 200 cases have been recorded until 2018 [1]. Matsumoto has identified a total of 102 Japanese cases from literature in the period between 1977 and 2013 [3]. Patients with TINU syndrome can present with systemic symptoms (fever, fatigue, malaise, asthenia, or headache), uveitis (bilateral eye pain, redness, blurred vision, or photophobia), and tubulointerstitial nephritis (rise in serum creatinine and urinary protein). Noncaseating granulomata were found in 13% of renal biopsy specimen [4].

Toxoplasma gondii is an intracellular protozoan parasite with worldwide distribution that infects more than one-third of the global population [5]. The clinical presentation of this parasite varies from asymptomatic in healthy individuals to neurological symptoms (encephalitis [6], meningitis), ocular symptoms (uveitis, such as posterior uveitis) [6, 7], myocarditis, pneumonitis, or opportunistic infections mostly in immunocompromised hosts. Although the renal manifestation of Toxoplasma infection is not frequent [8‐10], Toxoplasma infection is listed as a differential diagnosis of acute tubulointerstitial nephritis (TIN) [11] or of granulomatous interstitial nephritis [10]. Even in immunocompetent hosts, some (10–15%) [12‐15] individuals develop acute systemic manifestations. Most frequent symptoms are lymph node enlargement (94.6%), asthenia (86.5%), headache (70.3%), and fever (67.6%). Retinochoroiditis (10.8%) is also present in the analysis of 37 immunocompetent adults with acute acquired toxoplasmosis [16]. The severity of subacute toxoplasmosis of the primary infection may vary depending on the virulence of the strain or the amount of inoculum [17]. Although most of the symptoms in immunocompetent adults are self-limited and last from a few weeks to months [16, 18], life-threatening pneumonia or death has also been reported [19].

The prevalence of recent infection of Toxoplasma in immunocompetent adults is best studied with pregnant women. Primary infection at early pregnancy is well known to cause congenital toxoplasmosis. The positive rate of both immunoglobulin G (IgG) and immunoglobulin M (IgM) specific to Toxoplasma gondii in pregnant women varies worldwide: New Zealand, South Korea, USA 0.1–0.5%, Japan 1.0–1.5% [20, 21], or 3.8% [22], Africa, and Eastern Mediterranean 2–5% [21]. To make matters more complicated, Toxoplasma IgM can persist for several months [23‐27] or years [28] after the acute phase of primary infection (recent infection). Toxoplasma IgG avidity test is a key tool to distinguish “true” recent infection from distant infection, widely used for the screening of pregnant women. Among the initially screened IgM-positive pregnant women, as much as 59% (in Brazil) [29], 56% (in Turkey) [30], and 71.4% (in Japan) [31, 32] of them are reported to have a higher titer of IgG avidity, indicating distant infections of more than 5 months before [33]. This high frequency of persistent IgM in the initially screened IgM-positive population is one of the reasons for the lack of reliability in serological tests of Toxoplasma [34].

In the diagnosis of an autoimmune disease, differential diagnosis of dozens of systemic diseases including infections are required. Some infections are difficult to exclude because of symptoms similar to a suspected autoimmune disease. A combination of TINU syndrome and Toxoplasma gondii infection is one of them. If the IgM of Toxoplasma-specific antibody is present, the diagnostic processes become more challenging. Such cases might be misdiagnosed as TINU syndrome with coexisting active toxoplasmosis, or underdiagnosed as just toxoplasmosis. Differential diagnosis of TINU syndrome and interpretations of Toxoplasma serological tests in immunocompetent hosts will be discussed. The chances of encountering this combination might not be so rare considering the worldwide prevalence of Toxoplasma gondii.

A 34-year-old Japanese male with a medical history of gastric ulcer for 20 years, regular use of esomeprazole for the last 3 years, no known allergies, and no family history of kidney or eye disease presented to his local emergency department with complaints of having 2 days of 40 ℃ fever, headache, myalgia, general fatigue, and vomiting. These symptoms developed 2 days after an incised finger wound with a small amount of bleeding due to an injury during his sewage plumber work. A rapid test for influenza A and B antigens was negative; owing to concern for bacterial infection, he was started on amoxicillin and ibuprofen. His symptoms did not improve for 5 days, and he was referred to the neurology department of another hospital on day 6 of illness. On admission, he was alert. The headache and neck pain were triggered by his movement. His temperature was 38.5 °C, heart rate 88 beats/minute, and blood pressure 133/69 mmHg. Although the finger exhibited no redness, swelling, or abscess formation, physical examination revealed bilateral cervical and inguinal lymphadenopathy with tenderness. As meningeal irritation signs, neck stiffness was positive, and Kernig sign was positive at 60 degrees. No other neurological deficits were noted. White blood cell (WBC) count was 8200/mm³, with 70% neutrophils, 12.5% lymphocytes, 6.0% eosinophils, and 9.3% monocytes. Serum creatinine (Cre) was 0.91 mg/dL (80 μmol/L), and blood urea was 6.0 mg/dL (2.1 mmol/L). Erythrocyte sedimentation rate was 55 mm/hour, and serum C-reactive protein (CRP) was 11.58 mg/dL. Urine was negative for glucose and protein, the sediment contained < 1 white cell and < 1 red cell per high-power field, and two blood cultures were negative. Computed tomography (CT) scan of the brain did not identify any source of fever. A lumbar puncture was also performed in the neurology department. His cerebrospinal fluid (CSF) was clear and colorless. Initial pressure was high at 235 mmH₂O. CSF cell count was 1 × 10⁶ cells/L (1/μL) without red blood cells, glucose level was 3.66 mmol/L (66 mg/dL) [plasma glucose level 5.55 mmol/L (100 mg/dL)], and protein level was 0.31 g/L (31 mg/dL); no organisms were observed on Gram stain. No bacterial growth was detected in bottles of CSF and in bottles of blood. Then, treatment with oral levofloxacin 500 mg/day was initiated on day 6 of illness. Nonsteroidal antiinflammatory agents/drugs (NSAIDs), that is, diclofenac sodium suppositories 25 mg, were also administered three times a day for a week until remission of high fever on day 13 of illness (Fig. 2c). After the initiation of the treatment, contrary to the improvement of the inflammatory findings and parameters, kidney function deteriorated. Serum CRP levels were 11.58, 9.01, and 0.67 mg/dL, and serum Cre levels were 0.98, 1.28, and 2.74 mg/dL on day 6, 9, and 17 of illness, respectively. WBC count was 10,600/mm³, with mild elevated 12.5% eosinophil (reference value < 6.0%) on day 11. There was no skin eruption on extremities. Levofloxacin and esomeprazole were discontinued on day 17, and rapid reduction of kidney function prompted a transfer to our hospital on day 20 of illness for further evaluation and management (Fig. 2a,b). On admission, he had no fever and no complaints. There was no weight increase or pretibial pitting edema. The finger cut had healed without any scars or redness, and bilateral cervical and inguinal lymphadenopathy had diminished with little tenderness. Laboratory studies showed a WBC count of 10,000/mm³, with 60% neutrophil, 25% lymphocytes, 8.0% eosinophils, and 4.0% monocytes. Erythrocyte sedimentation rate was 22 mm/hour, serum CRP was 0.85 mg/dL, serum Cre was 2.09 mg/dL (185 umol/L), blood urea was 27.3 mg/dL (9.4 mmol/L), serum beta-2-microglobulin was 3.8 mg/L (reference value < 2.0 mg/L), urinary beta-2-microglobulin was 1589 ug/L (reference value < 229 ug/L), and urinary N-acetyl-β-d-glucosaminidase (NAG) was 7.9 IU/L (reference value < 6.9 IU/L). The results of laboratory tests showed that the levels of sodium, potassium, chloride, calcium, total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and uric acid were normal. IgG was 1073 mg/dL, immunoglobulin A (IgA) was 129 mg/dL, and IgM was 78 mg/dL. Urine remained negative for glucose and protein, and the sediment contained 0–1 white cell and 0–1 red cell per high-power field. Serum cystatin C measurement was 1.79 mg/L (reference value 0.57–1.01 mg/L), and glomerular filtration rate (GFR) was 61 mL/min/m². His fractional excretion of sodium (FeNa) was elevated to 2.1% (reference value < 1%). Renal sonography revealed normal level in resistance index.

A percutaneous renal biopsy performed on day 22 of illness revealed focal or belt-like distribution of numerous mononuclear cell infiltrates in the interstitium, associated with focal tubular atrophy, tubulointerstitial edema, and mild tubulitis. The moderate diffuse interstitial inflammation was composed of lymphocytes and eosinophils with mild fibrosis (Fig. 1b). Four interstitial granulomas composed of lymphocyte, plasma cell, macrophage, epithelioid cells, and multinucleated giant cells were identified (Fig. 1a). Glomerular and vascular structures were well preserved. Immunofluorescence showed no evidence of IgG, IgA, IgM, or immune complex deposition. Acid-fast staining for Mycobacterium was negative, and Grocott staining for detection of fungi was also negative. Angiotensin-converting enzyme (ACE) level was normal (11.4 U/L) (reference value 8.3–21.4 U/L). Chest X-ray and computed tomography did not reveal any abnormal masses, or mediastinum or hilar lymphadenopathy in the lung. Gallium scintigraphy did not show any abnormal accumulations. Saxon test results were normal (5.10 g/2 minutes) (reference value > 2.00 g/2 minutes). Anti-neutrophil cytoplasmic antibody (ANCA), MPO-ANCA, PR3-ANCA, anti-nuclear antibody (ANA), anti-SS-A/SS-B, anti-beta-2GPI, anti-RNP, anti-Sm, anti-dsDNA, anti-ssDNA, anti-Scl70, and anti-glomerular basement membrane (anti-GBM) antibodies were negative. IgG4 was at a normal level, soluble IL-2 receptor was 1050 U/mL (reference value 157–474 U/mL), and IgG-, IgA-, and IgM-specific antibodies against Chlamydia did not indicate a recent infection. Serologies for human immunodeficiency viruses (HIVs) 1 and 2, hepatitis B, and hepatitis C were negative. Anti-Treponema pallidum was negative, Epstein–Barr (EBV), mumps, and cytomegalovirus (CMV) serologies were not compatible with acute infection. According to these findings, we diagnosed the patient with granulomatous interstitial nephritis.

On day 29 of illness, eye pain, conjunctival hyperemia, tenderness, photophobia, and blurred vision appeared in both eyes. Best-corrected visual acuity (BCVA) was 1.2 in the right eye and 1.5 in the left eye. Intraocular pressures were normal (right 11 mmHg/left 14 mmHg) with deep anterior chamber. Slit-lamp examination revealed iritis and keratic precipitation (corneal endothelial inflammatory precipitates/deposits) in both eyes. Anterior chamber cells were 1+ right and 0.5+ left. Dilated fundoscopic examination revealed that retina and vitreous body had nonspecific findings. No fever and no lymphadenopathy were observed. Hence, the diagnosis of acute tubulointerstitial nephritis and bilateral uveitis (TINU) syndrome was made, and ophthalmic steroid therapy was initiated (Fig. 2b, c). Symptoms of uveitis, eye pain, redness, and blurred vision disappeared in 1 week. Keratic precipitations were reduced in 1 week, and disappeared in 2 weeks. His serum Cre level gradually improved to 1.29 mg/dL on day 44 of illness without any systemic medical interventions, and systemic steroid therapy was not provided throughout the course of the disease. Mild elevation of eosinophils was also gradually improved. Percentage of peripheral eosinophils/total WBC count were 8.0%/10000, 11.6 %/6700, and 5.0%/7600 on day 20, 24, and 44 of illness, respectively.

To rule out toxoplasmosis, which could also develop into lymphadenopathy, meningitis, and uveitis, Toxoplasma-specific IgG and IgM titers were evaluated on day 37 of illness, and revealed to be both positive 219 IU/mL (reference value < 6 U/mL) and 4.2 IE/mL (reference value < 0.8 U/mL) respectively. He had a dog for a pet, but not a cat. Despite the positivity of Toxoplasma IgM antibody, the bilateral uveitis responded well to the ophthalmic steroid therapy, lymphadenopathy disappeared,and no signs of meningitis was observed. We decided that antimicrobial therapy was not needed, and he was discharged on day 44 of illness. Drug-induced lymphocyte stimulation test (DLST) or lymphocyte transformation test (LTT), performed by a commercially based clinical diagnostic testing service (SRL, Inc., Tokyo, Japan), confirmed that the patient had a negative stimulation index (SI) score for levofloxacin, esomeprazole, ceftriaxone, and amoxicillin, while he had a high SI score exclusively for diclofenac sodium of 207% (reference value < 180%).

After discharge, uveitis recurrence was not detected, and ophthalmic steroid was terminated after 2 months of use. However, the titer of IgM of Toxoplasma remained at a high level for an additional 6 months; we were not sure whether Toxoplasma infection was implicated in this TINU syndrome (Fig. 2d). To address the question, Toxoplasma IgG avidity test was performed with serum sample of day 20 of illness stocked in freezer, and with fresh serum sample from day 239 of illness. The test was performed by a laboratory company (SRL) using Platelia (TM) TOXO IgG AVIDITY (Bio-Rad) according to the manufacturer’s protocol. In brief, optical density (OD) indicating Toxoplasma IgG in serum was measured by enzyme-linked immunosorbent assay (ELISA) after dissociating the link between antibody and antigen. Urea was used as the dissociating agent. Target antigen of the ELISA was purified from Toxoplasma gondii RH strain. Avidity Index (AI) was measured by the ratio of OD(dissociating agent treated) to OD(dissociating agent untreated). IgG AI of the above samples was 0.62 (day 20) and 0.66 (day 239) (reference value: low AI < 0.4, mid 0.4 ≤ AI < 0.5, high 0.5 ≤ AI), indicating a chronologically distant infection of more than 5 months before fever onset. Hence, we determined that the pathogenesis of TINU syndrome in our case was not implicated with a recent infection of Toxoplasma.

No recurrence of renal dysfunction was observed in the 18 months of follow-up; serum Cre levels were 1.21, 1.03, and 1.04 mg/dL on day 71, 92, and 239 of illness, respectively. Urinary beta-2-microglobulin was reduced to 234 μg/L (reference value < 229 μg/L) on day 204 of illness. HLA typing showed HLA-A3101, HLA-A3303, HLA-B4002, HLA-B4403, HLA-DR0802, HLA-DR1302. HLA-DQB1 0302, and HLA-DQB1 0604, none of which was reported to have strong association with TINU syndrome.

To diagnose TINU syndrome, differential diagnosis of infections and dozens of other systemic diseases are required. Among infections, Toxoplasma gondii is a pathogen with considerable prevalence on a global scale. Since IgM of Toxoplasma is known to persist in many cases [32], the chances of encountering patients with TINU syndrome with Toxoplasma IgM like our patient might not be so rare. Our case illustrates the difficulties in determining the pathogenic contribution of Toxoplasma gondii in a case of lymphadenopathy and meningitis followed by TINU syndrome. IgG avidity test seemed to rule out recent infection of Toxoplasma and led us to conclude that TINU syndrome in our case was not implicated with a recent infection of Toxoplasma. However, this process of interpretation may not be enough for a precise understanding of the infection profile of Toxoplasma in similar situations. The limitations of current commercial serological tests are also discussed here.

This case illustrates the difficulty in determining the infection profile of Toxoplasma gondii in the diagnosis of TINU syndrome. Performing the IgG avidity test in a timely manner is recommended to determine the chronological assessment of the putative Toxoplasma gondii infection. However, these serological examinations still have limitations in their precise determination of the infection profile. Therefore, careful monitoring and extended follow-up of such patients are critical.