Multisystem Inflammatory Syndrome in Adults and Severe Toxoplasmosis: Similar Clinical Presentations, Potentially Severe Outcomes.

We report a case of a 21-year-old previously healthy man who developed severe toxoplasmosis with chorioretinitis and myositis 2 months after receiving corticosteroids for presumed multisystem inflammatory syndrome in adults, in the setting of a recently acquired acute Toxoplasma infection, likely during a trip to Latin America.

In the coronavirus disease 2019 (COVID-19) era, multisystem inflammatory syndrome in adults (MIS-A) and in children (MIS-C) have become potentially life-threatening conditions [1]. Acute toxoplasmosis, particularly in patients infected with atypical more virulent Toxoplasma gondii strains, is associated with high morbidity and mortality [2-7]. We report a case of a 21-year-old previously healthy man who developed severe toxoplasmosis after receiving corticosteroids for presumed MIS-A, in the setting of a recently acquired acute Toxoplasma infection. MIS-A and severe toxoplasmosis unfolded during 3 hospitalizations over a 3-month period. This case underscores the need to consider toxoplasmosis, among other pathogens, when treating patients for acute COVID-19 or MIS-A/MIS-C, especially with prolonged courses of immunosuppressive medications. Appropriate diagnostic evaluation and prompt initiation of anti-Toxoplasma treatment can be life-saving.

CLINICAL CASE

A 21-year-old previously healthy, United States–born, nonobese white man presented to an adult emergency department with 7 days of fever, headache, generalized myalgias, arthralgias, and diarrhea beginning 1 day after returning to the United States from a 5-week trip to Ecuador and Costa Rica.

First Hospitalization

On day of illness (DOI) 8, the patient presented in shock, was febrile (39.8°C [103.7°F]) and profoundly hypotensive, and responded to fluid resuscitation. His physical examination was notable for extremity tremors. Laboratory results demonstrated transaminitis, hyponatremia, and elevated lactate, C-reactive protein (CRP), and procalcitonin (Figure 1). Blood and urine cultures were obtained and empirical antimicrobials were started with vancomycin, piperacillin-tazobactam, and azithromycin. Pending results of malaria thick and thin smears and additional zoonotic testing, he was prescribed atovaquone-proguanil and doxycycline, respectively (Figure 1). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal polymerase chain reaction (PCR) was positive. Within 24 hours, he developed pleuritic chest pain and hypoxemia. Chest radiograph was normal, but chest computed tomography (CT) on DOI 9 revealed diffuse bilateral confluent ground glass opacities, numerous centrilobular nodules, bilateral trace pleural effusions, and mildly enlarged mediastinal and bilateral hilar lymph nodes (Figure 2). Remdesivir and dexamethasone were started but were discontinued 48 hours later, after resolution of hypoxemia and fever; additional data confirmed a low SARS-CoV-2 viral load (high cycle threshold value of 36) and positive SARS-CoV-2 spike protein immunoglobulin G (IgG) antibodies (after 2 COVID-19 messenger RNA vaccine doses). High-sensitivity troponin was elevated, suggesting myocarditis, whereas B-type natriuretic peptide was normal. Transthoracic echocardiography revealed mild global hypokinesia, and electrocardiography was normal.

Figure 1.

Clinical course: Hospitalizations and laboratory and imaging evaluations. Additional laboratory results: Day of illness (DOI) 23: cerebrospinal fluid (CSF) white blood cell count (WBC), 37 cells/µL (73% lymphocytes); red blood cell count (RBC), <3 cells/µL; protein, 103 mg/dL; glucose, 53 mg/dL; CSF cultures, negative; CSF meningitis/encephalitis multiplex polymerase chain reaction (PCR) panel, negative; CSF Venereal Disease Research Laboratory test, negative. DOI 84: CSF WBC, 13 cells/µL (95% lymphocytes); RBC, 1 cell/µL; protein, 62 mg/dL; glucose, 95 mg/dL; CSF meningitis/encephalitis multiplex PCR panel, negative; CSF Toxoplasma DNA PCR, negative. DOI 82: Toxoplasma immunoglobulin M (IgM), >160 IU/mL (reference value, <7.2 IU/mL); Toxoplasma immunoglobulin G (IgG), > 400 IU/mL (reference value, <7.2 IU/mL). Confirmation at the Remington Laboratory for Specialty Diagnostics: Toxoplasma IgG dye test, 1:32 000 (reference value, <1:16), Toxoplasma IgM enzyme-linked immunosorbent assay (ELISA), 11.5 (reference positive value, ≥2.0), Toxoplasma immunoglobulin A ELISA, >21.8 (reference positive value, ≥2.1), and Toxoplasma IgE ELISA >18.8 (reference positive value, ≥1.9); Toxoplasma IgG avidity, 6 (low; reference value for low IgG avidity, <20). Metagenomics next-generation sequencing (mNGS) in plasma: positive for T gondii (5491.6 molecules per plasma microliter). mNGS also detected Epstein-Barr virus and cytomegalovirus, which were not considered to be of clinical significance. Reference ranges and units: albumin, 3.4–5.2 g/dL; aldolase, 1.5–8.1 U/L; alanine aminotransferase, <36 IU/L; aspartate aminotransferase, 15–50 IU/L; B-type natriuretic peptide, <100 pg/mL; creatinine phosphokinase, <289 U/L; C-reactive protein, <1 mg/dL; d-dimer, <0.5 µg/mL; erythrocyte sedimentation rate, <15 mm/hour; ferritin, 31–294 ng/mL; hemoglobin, 13.5–18 g/dL; hematocrit: 41%–53%; high-sensitivity troponin, <53 ng/L; lactate, 0.5–1.6 mmol/L; lactate dehydrogenase, 325–650 U/L; procalcitonin, <0.5 ng/mL; platelets, 142–508 K/µL; sodium, 135–145 mmol/L; WBC, 4.5–11 103/µL. Abbreviations: Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B-type natriuretic peptide; Cards, cardiology outpatient evaluation; cMRI, cardiac magnetic resonance imaging; CPK, creatine phosphokinase; CRP, C-reactive protein; CT, computed tomography; CXR, chest radiograph; ECG, electrocardiogram; ECHO, echocardiogram; ESR, erythrocyte sedimentation rate; hs troponin, high-sensitivity troponin; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; NP, nasopharyngeal; Neuro, neurology outpatient evaluation; PCR, polymerase chain reaction; PCT, procalcitonin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; seq, sequences (by mNGS); Toxo, Toxoplasma; U, urine; V, vitreous fluid; WBC, white blood cell.

Figure 2.

A, Chest computed tomography (CT) (day of illness [DOI] 9): diffuse confluent ground glass opacities of both lungs (yellow arrows, first panel), bilateral trace pleural effusions, and enlarged hilar lymph nodes (yellow arrows, second panel). B, Cardiac magnetic resonance imaging (MRI) (DOI 24): patchy areas of diffuse myocardial enhancement on T1 imaging (yellow arrows, first two panels) and an elevated calculated myocardial extracellular volume (35%; reference value, <25%), suggesting diffuse interstitial expansion. T2 mapping also showed diffuse myocardial edema (white arrow, third panel) when compared with normal skeletal muscle (black arrow, third panel). C, MRI orbits (DOI 82): mild elevation of both optic nerve heads and several hyperintense fluid-attenuated inversion recovery (FLAIR) plaques along the inner margins of both globe walls; largest on right is just below the optic nerve head (7 mm ×  2 mm × 10 mm) and on left along the lateral aspect of the globe wall (6 mm × 4 mm × 2 mm), suggesting chorioretinitis (yellow arrows, both panel). D, Brain MRI (with and without contrast) (DOI 83): suggestive of demyelination with patchy increased T2 FLAIR signals in the right posterior frontoparietal centrum semiovale, internal restricted diffusion, minimal enhancement, and increased FLAIR signal of globus pallidus (yellow arrow, D1), axial images associated with mild restricted diffusion (yellow arrow, D2), and minimal internal enhancement on T1 postcontrast (yellow arrow, D3). Several tiny foci of increased FLAIR signal in the left globus pallidus (yellow arrow, D4) and increased T2 FLAIR signal involving the cortex at the depth of the left superior frontal sulcus without restricted diffusion (yellow arrow, D5).

Additional epidemiologic history included spending time in the Amazon jungle 14 days prior to symptom onset, consuming local foods including tapir (no raw meat), and drinking from local water sources. Stool PCR was positive for Giardia. While awaiting the results of possible zoonotic infections, he completed 10 days of doxycycline (Figure 1). Blood cultures were sterile. Given also rapid clinical improvement, antibiotics (except doxycycline) were discontinued after 48 hours. He was discharged home on DOI 11 with down-trending high-sensitivity troponin.

Second Hospitalization

He was readmitted 9 days after discharge (DOI 20), with recurrence of fever (38.9°C [102°F]), generalized weakness, fatigue, shortness of breath with exertion, headache, neck pain, orthostatic symptoms, worsening fine tremor in extremities, myoclonic jerks, and unstable gait, but no meningismus or encephalopathy. He was again in shock, poorly responsive to fluids, and required fludrocortisone and midodrine. Laboratories revealed hyponatremia, ongoing troponin leak, and elevated ferritin, though down-trending CRP and liver enzymes. Head and neck CT and brain and spine magnetic resonance imaging (MRI) were normal. Cerebrospinal fluid (CSF) examination showed normal opening pressure but elevated protein and a lymphocytic pleocytosis. CSF cultures and infectious diseases diagnostics were negative (Figure 1). Cardiac MRI (cMRI) on DOI 24 confirmed myocarditis according to Lake Louise criteria [8], with mild left ventricular systolic dysfunction, diffuse myocardial inflammation/edema, nonischemic fibrosis, and interstitial expansion (Figure 2) despite normal Holter monitor. Concern for post SARS-CoV-2 MIS-A prompted initiation of intravenous immunoglobulin and solumedrol on DOI 25 (Figure 1). Fevers resolved and was discharged after 11 days on a prolonged prednisone taper, lisinopril, low-dose aspirin, exercise restriction, and outpatient follow-up with cardiology and neurology.

After discharge, he continued to have generalized fatigue, myalgias, muscle weakness, and worsening myositis, including a 10-fold increase in creatine kinase, new splenomegaly, and ongoing tremors, partially responsive to clonazepam. Repeat cMRI on DOI 68 showed mildly decreased left ventricular systolic function, but myocardial edema and delayed enhancement had resolved.

On DOI 70, he complained of blurry vision and eye floaters. Fundoscopic examination revealed bilateral focal areas of chorioretinitis, papillitis, vitritis, intraretinal hemorrhage, bilateral optic nerve disc edema, and retinal whitening. Thereafter, he was hospitalized for further evaluation.

Third Hospitalization

Toxoplasma immunoglobulin M (IgM) and IgG serologies were sent and were both highly positive. Confirmatory testing at the Remington Laboratory for Specialty Diagnostics (Palo Alto, California; www.sutterhealth.org/RemingtonLab) showed high-positive Toxoplasma IgG dye test, IgM, IgA, and IgE titers and low IgG avidity suggesting of a very recent acute Toxoplasma infection, likely acquired during his trip to Latin America. Toxoplasma gondii was detected by PCR from vitreous fluid and urine, and plasma metagenomics next-generation sequencing (mNGS) cell-free DNA (Karius, Inc, Redwood City, California) [9, 10] also detected T gondii (Figure 1). MRI of the orbits confirmed bilateral posterior uveitis (Figure 2). A second lumbar puncture on DOI 84 showed down-trending CSF pleocytosis and CSF protein. Brain MRI on DOI 85 showed findings consistent with postinfectious demyelination (Figure 2), while the spinal MRI was normal. MRI of the lower extremities showed myositis. On DOI 86, anti-Toxoplasma therapy with pyrimethamine, sulfadiazine, and leucovorin was started. At 4-week follow-up there was improvement in visual and retinal findings, resolution of fatigue and myalgias, improvement of tremors and splenomegaly, and normalization of troponin, liver function tests, and creatine kinase.

DISCUSSION

Acute COVID-19 and MIS-A/MIS-C pose a diagnostic and management challenge for clinicians globally. Despite case definitions for MIS-A/MIS-C, there is a significant overlap in symptoms, clinical manifestations, and laboratory evidence of inflammation with other syndromes and infections. Given that COVID-19 and MIS-A/MIS-C may require management with immunosuppressive or immunomodulatory therapies, healthcare providers should prudently consider serologic screening for toxoplasmosis, among other infectious agents, prior to initiating immunosuppressive therapies. Although our patient had risk factors for toxoplasmosis (travel to the Amazon, consuming local food and drinking from local water sources), absence of conventional risk factors should not exclude the diagnosis of acute toxoplasmosis if clinical presentation is compatible [11, 12]. A common error is the failure to consider toxoplasmosis in the differential diagnosis of such patients in the absence of conventional risk factors for toxoplasmosis (eg, changing cat litter or eating raw meat). Toxoplasma gondii is a ubiquitous parasite and the source of the T gondii infection (eg, through ingestion of soil-contaminated food) can easily remain unnoticed. Almost 50% of patients with acute toxoplasmosis fail to report classic risk factors for toxoplasmosis [11, 12].

Without histopathologic examination of myocardial, lung, or muscle tissue biopsy and Toxoplasma molecular studies during the first 2 hospitalizations, it is difficult to confirm the exact etiology of this patient’s initial presentation (MIS-A vs acute severe toxoplasmosis [2-4] vs combination of the above). It is possible that initially the patient had MIS-A, with some response to 2 days of dexamethasone. However, after stopping corticosteroids (after the first hospitalization), his MIS-A symptomatology rapidly worsened, with development of myocarditis, CSF abnormalities, and hyperferritinemia; these only partially improved with subsequent immunosuppressive and immunomodulatory treatment. This patient's initial clinical presentation could have been considered consistent with MIS-A, meeting the Centers for Disease Control and Prevention (CDC) case definition [13], including fever ≥38°C for ≥24 hours, at least 3 MIS-A clinical criteria, with at least 1 being a primary criterion (primary criterion: severe cardiac illness with myocarditis/ventricular dysfunction, and 3 of 4 secondary criteria: new onset of neurologic symptoms with CSF pleocytosis, shock/hypotension and abdominal pain [that persisted despite treatment for giardiasis]), laboratory evidence of inflammation (elevated CRP, procalcitonin, ferritin), and evidence of SARS-CoV-2 infection (positive SARS-CoV-2 PCR and positive SARS-CoV-2 IgG antibodies). The CDC case definition for MIS-A/MIS-C includes as a criterion the absence of alternative plausible diagnoses [13]. However, in this patient, the toxoplasmosis diagnosis was not initially considered and therefore the patient was not initially tested for T gondii.

Alternatively, it is possible that patient initially had acute severe toxoplasmosis, likely acquired during his trip to Latin America (with or without MIS-A) that initially partially responded to empirical antibiotic treatment. Doxycycline has some anti-Toxoplasma activity [14]; however, it is not a conventional anti-Toxoplasma treatment. The patient had also received azithromycin and atovaquone as part of his initial antibiotic management; both of these medications have anti-Toxoplasma activity. Severe toxoplasmosis presenting with a septic shock–like picture, pneumonia with ground glass opacities, myocarditis, hepatitis, myositis, and systemic inflammation have been reported even in immunocompetent individuals, particularly if more virulent T gondii strains are implicated, such as those found in Latin America [2-7]. This case also illustrates that, in the COVID-19 era, clinicians should beware of anchoring bias in their clinical reasoning and maintain a broad differential when indicated. In several parts of the world (eg, in Latin America and North America from wild-game T gondii strains), a number of patients present with severe toxoplasmosis caused by virulent/atypical strains [15]. The clinical manifestations of toxoplasmosis in such settings can be atypical. Patients presenting with systemic inflammation following travel to regions where more virulent T gondii strains are circulating should be screened for toxoplasmosis.

Independent of the exact etiology of the patient's presentation, the prolonged corticosteroid course contributed to the development of severe toxoplasmosis. The diagnosis was established only during his third hospitalization, concomitant with the development of acute chorioretinitis, worsening myositis, transaminitis, and new splenomegaly. Regarding his myocarditis, this could have been due to MIS-A, acute toxoplasmosis, or a combination of the above. The clinical and laboratory findings of myocarditis (detected at presentation) did not follow the usual course and response to treatment of MIS-A–associated myocarditis. Troponin, creatine phosphokinase, and symptomatology resolved only after 2–4 weeks of anti-Toxoplasma therapy. Regarding his neurologic findings, these could be due to MIS-A, central nervous system (CNS) toxoplasmosis, postinfectious sequelae (post–COVID-19 or post-toxoplasmosis), or a combination of the above. The patient had tremors, headaches, myoclonic jerks, and unsteady gait along with CSF pleocytosis and elevated CSF protein early in the course, but abnormal brain MRI findings, suggestive of postinfectious demyelination, were found on DOI 85. Acute disseminated encephalomyelitis has been reported both with CNS toxoplasmosis [16, 17] and MIS-A/MIS-C [18]. The fact that CSF T gondii PCR was negative on DOI 84 does not exclude the possibility of CNS toxoplasmosis earlier in the patient's course.

Severe toxoplasmosis [2-7] can mimic the clinical manifestations of severe COVID-19 or MIS-A/MIS-C, can present concomitantly with COVID-19 or MIS-A/MIS-C, or can develop as sequelae of prolonged immunosuppressive treatment for COVID-19 or MIS-A/MIS-C. A high index of suspicion for toxoplasmosis should be considered in COVID-19 and/or MIS-A/MIS-C patients who do not respond or who clinically worsen with immunosuppressive therapy. Testing should be performed by both serologic and molecular methods, including T gondii PCR from blood, bronchoalveolar lavage, urine, CSF, other body fluids or tissue biopsies, and by mNGS from plasma, with the latter having also the possibility to explore infections in diverse body sites and infections from other pathogens. Treatment should be considered accordingly with oral pyrimethamine/sulfadiazine/folinic acid (first line anti-Toxoplasma therapy) or intravenous trimethoprim-sulfamethoxazole (alternative therapy). Factors contributing to severe immunosuppression in COVID-19 include profound lymphopenia and/or treatment with immunosuppressive medications (eg, corticosteroids) and/or immunomodulatory agents [19, 20]. Implementation of routine screening for toxoplasmosis should be considered before initiating immunosuppressive treatment for COVID-19 [21, 22]. Moreover, chemoprophylaxis with trimethoprim-sulfamethoxazole should be considered in selected T gondii–seropositive patients with COVID-19 or MIS-A/MIS-C, particularly if high-dose immunosuppressive treatment will be used for prolonged periods (eg, >2 weeks).