Parvovirus B19 Infection: A Vasculitis Masquerade in an Elderly Patient

Abstract

Patient: Male, 78-year-old

Final Diagnosis: Human parvovirus B19 infection

Symptoms: Fever • edema • skin rash

Clinical Procedure: None

Specialty: Immunology • Infectious Diseases • General and Internal Medicine • Microbiology and Virology

Objective:

Unusual clinical course

Background:

The profound ability of viral infections to convincingly mimic vasculitis, thereby pathologically influencing vessels of any caliber, is undeniably significant. Notably, adult patients with B19V infection frequently experience joint pain and cutaneous eruptions, which are ostensibly immune responses to the infection and necessitate careful differentiation from autoimmunity. Conversely, vasculitis syndromes represent an amalgamation of diseases characterized by vascular inflammation, predominantly classified based on the impacted vessels’ size and location. Although the expedited diagnosis and therapeutic management of vasculitis are paramount, many conditions, including infectious diseases, can potentially masquerade as vasculitis, necessitating rigorous differential diagnosis.

Case Report:

A 78-year-old male patient presented with fever, bilateral leg edema, skin rash, and foot numbness to the outpatient department. Blood investigations showed elevated inflammatory parameters, and urinalysis showed proteinuria and occult blood presence. We considered SVV, particularly microscopic polyangiitis, which causes acute renal injury, as the provisional diagnosis. Blood investigations, including auto-antibodies and a skin biopsy, were performed. However, his clinical symptoms resolved spontaneously before these investigation results were reported. Subsequently, the patient was diagnosed with B19V infection based on B19V immunoglobulin M antibody positivity.

Conclusions:

B19V infection mimics vasculitis. Even in geriatric patients, particularly during B19V infection outbreaks, clinicians should conduct thorough interviews and examinations while contemplating the likelihood of B19V infection as a potential vasculitis mimic.

Background

Human parvovirus B19 (B19V) infection causes erythema infectiosum in children. However, the virus triggers many systemic manifestations, including cutaneous eruptions and arthralgia in adults; although these symptoms are somewhat atypical of erythema infectiosum, they are frequently superseded by predominant arthropathy, particularly in women [1]. The detailed mechanism responsible for this phenomenon is unknown [2]; however, the manifestation of erythema infectiosum and arthropathy are conjectured to result from the formation and subsequent deposition of immune complexes [1]. The characteristic B19V facial rash observed in children is rarely found in adults [3,4]. Additionally, B19V-induced post-infection acute glomerulonephritis can cause renal damage, albeit this consequence is relatively uncommon [5]. From a diagnostic perspective, B19V-associated arthralgia, skin rash, and nephropathy with fever in adults should be differentiated from autoimmune conditions. However, the immune response elicited by B19V infection could produce false-positive auto-antibodies, creating potential misidentification of B19V infection as an auto-inflammatory disorder [6,7]. Therefore, it is crucial to diagnose vasculitis promptly. Moreover, since various diseases can mimic the condition, differentiation from other entities is required. Infection can mimic vasculitis and affect vessels of any size. Viral infections, such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis B and C viruses, and HIV are known to mimic vasculitis [7]. However, the clinical manifestations of small vessel vasculitis (SVV) vary and can include systemic symptoms, such as fever and malaise, skin rashes, peripheral neuropathic symptoms due to tissue hemorrhage, and ischemia. Therefore, a differential examination is critical. Microscopic polyangiitis (MPA) is hypothesized to be SVV that is caused by an autoimmune abnormality involving antineutrophil cytoplasmic antibody (ANCA), although its definitive cause is unknown [8–10]. Renal involvement is the most common manifestation of severe MPA, and an early diagnosis is crucial because of the possibility of rapid progression and transition to end-stage renal failure [9].

Therefore, we report a case of B19V infection in an older adult patient who presented with typical SVV-like symptoms (fever, bilateral leg edema, skin rash, and numbness in the feet) but whose symptoms eventually resolved spontaneously.

Case Report

A 78-year-old male patient, who underwent treatment for hypertension (candesartan, 4 mg, and amlodipine, 2.5 mg, daily), presented to the hospital with complaints of fever, edema, and skin rash on both legs, with accompanying feet numbness. The patient reported feeling fatigued for 2 weeks before the initial hospital visit. He had a fever of 38.0°C and subsequently noticed bilateral leg edema and skin rash 4 days before his visit. On the morning of his hospital visit, he had difficulty walking independently because of numbness in both legs and came to the hospital in a wheelchair. On physical examination, he had a body temperature of 37.9°C, respiratory rate of 16 breaths/min, blood pressure of 130/74 mmHg, pulse rate of 112 beats/min, and peripheral capillary oxygen saturation of 98% breathing room air. He had bilateral pitting edema of the lower legs, extending from the knees to the feet, with concurrent livedo reticularis in the same area (Figure 1). An examination of the face, trunk, and arms revealed no skin rashes or purpura. Additionally, the patient had concerns of numbness on the plantar portions of both feet, which was aggravated by ankle joint movement, making walking difficult; however, he had no obvious muscle weakness. His deep tendon reflexes in both legs were normal. He had marked hyper-algesia of the plantar fascia but no abnormalities in positional and vibratory sensations. Furthermore, he did not report any joint pain in his arms or legs, there were no signs of arthritis, and no other abnormal physical findings were observed.

Figure 1.

(A) Bilateral pitting edema of the lower legs with concurrent livedo reticularis in the same area; (B) characteristics of the lesions.

Differential Diagnoses

We considered the following differential diagnoses based on the patient’s key clinical complaints: severe bacterial infection (infective endocarditis), viral infections (HIV, hepatitis B, hepatitis C, Epstein-Barr virus, SARS-CoV-2, and B19V), tuberculosis, syphilis, mycoplasma pneumonia, autoimmune diseases (systemic lupus erythematosus, Behcet’s disease, and sarcoidosis), and hematologic malignancies (malignant and intravascular lymphomas) (Table 1).

Table 1.

Differential diagnosis of this case.

Infection	Bacteria (IE) Viral (HBV, HCV, EBV, HIV, SARS-CoV-2, B19V) Tuberculosis Syphilis Mycoplasma pneumonia
Vasculitis (SVV)	AAV (MPA, GPA, EGPA) Immune complex SVV (anti-GBM disease, CV, IgA vasculitis, HUV)
Autoimmune	SLE, Behcet’s disease, sarcoidosis
Hematological malignancy	Malignant lymphoma, intravascular lymphoma

AAV – antineutrophil cytoplasmic autoantibody-associated vasculitis; B19V – human parvovirus B19; CV – cryoglobulinemic vasculitis; EGPA – eosinophilic granulomatosis with polyangiitis; GBM – glomerular basement membrane; GPA – granulomatosis with polyangiitis; HBV – hepatitis B virus; HCV – hepatitis C virus; HIV – human immunodeficiency virus; HUV – hypocomplementemic urticarial vasculitis; IE – infective endocarditis; MPA – microscopic polyangiitis; SLE – systemic lupus erythematosus; SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2; SVV – small vessel vasculitis.

Investigations

Blood tests showed an elevated inflammatory response (white blood cell count, 10 100/μL; C-reactive protein level, 11.3 mg/dL; and erythrocyte sedimentation rate, 55 mm/h), mild anemia (red blood cell count, 483×10³ cells/μL and hemoglobin, 12.9 mg/dL), and renal dysfunction (blood urea nitrogen, 25 mg/dL and creatinine, 1.19 mg/dL). We examined the patient for viral infections, and all test results except B19V-immunoglobulin M (IgM) were negative. Furthermore, cryoglobulin tested negative. His antinuclear antibody titer was 640-fold; however, test results for myeloperoxidase-ANCA and proteinase 3-ANCA were negative (Table 2).

Table 2.

Laboratory test results.

			(reference range)				(reference range)
WBC	10 100	/μL		STS	(-)
RBC	438	×104/μL		TPHA	(-)
Hb	12.9	g/dL		HBsAg, HBsAb	(-)
Plt	36.9	×104/μL		HCV	(-)
ESR	55	mm/h		HIV	(-)
TP	6.7	g/dL		CMV-IgM	(-)
Alb	3	g/dL		EBV-IgM	(-)
AST	54	IU/L		T-SPOT	(-)
ALT	34	IU/L		Mycoplasma-IgM	(-)
LDH	310	IU/L		SARS-CoV-2 PCR	(-)
BUN	25	mg/dL		B19V-IgM	4.76	Index	<0.8
Cr	1.19	mg/dL
Na	138	mEq/L		ANA	640	fold	<40
K	4.3	mEq/L		MPO-ANCA	<1.0	U/mL	0–3.4
Cl	101	mEq/L		PR3-ANCA	0.8		<2.0
C3	116	mg/dL	73–138	Anti-SS-A/Ro	<0.5	U/mL	<7.0
C4	16	mg/dL	11–31	Anti-ds-DNA	1.9	IU/mL	0–12
IgG	1607	mg/dL	861–1747	Anti-Sm Ab	0.6	U/mL	<7.0
IgA	201	mg/dL	93–393	Anti-RNP Ab	0.6	U/mL	<3.5
IgM	168	mg/dL	33–183	Lupus anticoagulant	0.8		<1.3
CRP	11.3	mg/dL	<0.3	aCL	13	U/mL	0–10
sIL-2R	1543	U/mL	333–587	Cryoglobulin	(-)

aCL – anticardiolipin; Alb – albumin; ALT – alanine aminotransferase; ALP – alkaline phosphatase; ANA – antinuclear antibody; ANCA – antineutrophil cytoplasmic antibody; AST – aspartate aminotransferase; B19V – human parvovirus B19; BUN – blood urea nitrogen; Cl – chlorine; Cr – creatinine; CMV – cytomegalovirus; CRP – C-reactive protein; ds – double-stranded; EBV – Epstein-Barr virus; ESR – erythrocyte sedimentation rate; Glu – glutamic acid; Hb – hemoglobin; HbsAg – surface antigen of the hepatitis B virus; HbsAb – hepatitis B surface antibody; HCV – hepatitis C virus; HIV – human immunodeficiency virus; Ig – immunoglobin; K – potassium; LDH – lactate dehydrogenase; LDL-Chol – low-density lipoprotein cholesterol; MPO – myeloperoxidase; Na – sodium; PCR – polymerase chain reaction; Plt – platelet count; PTH – parathyroid hormone; PR3 – serum anti-proteinase 3; RBC – red blood cells; RNP – ribonucleoprotein; SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2; STS – syphilis; TP – total protein; TPHA – treponema pallidum hemagglutination assay; WBC – white blood cells.

The urinalysis results were positive for protein (2+) and occult blood (2+). Microscopic examination revealed 5 to 9 erythrocytes per field of view and no obvious morphological abnormalities. The protein/creatinine ratio was 0.43 g/g.Cr (reference value, <0.15), indicating mild proteinuria.

Urine and blood cultures were negative for any microbial growth. Imaging studies showed no lymphadenopathy, hepatosplenomegaly, or possible focus of infection that could have caused the fever. Skin biopsies performed at the site of the livedo reticularis showed no sign of vasculitis or malignancy.

Three weeks after the onset of fever (hospitalization day 11), B19V-IgM by enzyme immunoassay was positive at 4.76 (negative, <0.8), and the diagnosis of acute B19V infection was confirmed.

Treatment

The patient was treated with oral acetaminophen (400 mg) during febrile episodes, and no other treatment was administered. Furthermore, the patient fully recovered without complications.

Discussion

B19V infection is a globally recognized infectious disease [1,2,11]. The prevalence of B19V antibodies in adults increases with age, from 40% to 60% in young adults to approximately 85% to 90% in older people [1,3]. More than half of B19V cases in adults are acquired from children because of the infection of a household member [1,6,12]. The skin rash of a B19V infection is characterized by the typical “slapped cheek” in children but is less and more common on the face and lower legs, respectively, in adults [1,3,11]. Various cutaneous manifestations, including erythematous skin rash, purpura, and livedo reticularis, have been reported in adults with B19V infection [3,4]. However, the incidence of these skin rashes has not been reported. Additionally, edema due to B19V infection varies from mild to generalized [13,14]. Furthermore, B19V infection causes renal disorders, such as acute glomerulonephritis and nephrotic syndrome, which frequently resolve spontaneously [5,11]. However, B19V blood tests can show false-positive results for auto-antibodies, such as antinuclear antibodies, ANCA antibodies, and rheumatoid factor [6,7]. These diverse clinical and laboratory outcomes are believed to be due to direct damage from the viral infection and immune complexes created because of induced auto-antibody production; however, the exact causative mechanism remains unknown [5,12] and could be similar to that of an autoimmune disease.

Generally, IgM in response to B19 appears 7 to 10 days after infection and remains positive for 2 to 4 months. B19V-IgM antibody detected via enzyme immunoassay can be used to diagnose acute or recent infection and is the mainstay of diagnosis in healthy hosts [1].

However, when clinical and general examination outcomes suggest SVV during provisional diagnosis, appropriate diagnostic tests should be performed expeditiously while considering the differential diagnoses. In the present case, we considered MPA to be a disease that could not be overlooked owing to its potential to cause rapid deterioration of renal function.

MPA has been hypothesized to be an autoimmune abnormality-induced SVV involving ANCA, although its definitive cause remains unknown [8–10,15]. It is reported to have an incidence rate and a prevalence of 0.5 to 24.0 and 9 to 94 per million, respectively, occurring predominantly in middle-aged and older adults, without sex differences [16]. In addition to systemic symptoms, such as fever, fatigue, and weight loss, MPA is associated with arthralgia, skin rashes (palpable purpura and livedo reticularis), and peripheral neuropathy [8]. Renal involvement is the most common manifestation of severe MPA, and an early diagnosis is crucial due to the possibility of rapid progression and transition to end-stage renal failure [9]. Furthermore, neuropathy is present in 50% of patients with MPA [17]. We assumed SVV, particularly MPA, and performed the tests necessary to evaluate the MPA categorization criteria to enable a rapid diagnosis [10]. However, the results did not indicate MPA and were as follows: Computed tomography showed no lung abnormalities, skin biopsy showed no abnormal findings, and the ANCA result was negative.

In this case, there was no history of contact with children; however, B19V infection was prevalent in the community at that time [18].

Moreover, spontaneous improvement in skin rash, livedo reticularis, and bilateral edema of the limbs was observed. Although joint pain is common in adults with B19V infection, it was not present in this case. The clinical manifestations of B19V in adults vary widely, making diagnosis based on the physical examination outcomes alone an arduous task. Peripheral neuropathy is an uncommon symptom of B19V infection; however, in this case, the patient had numbness localized to the plantar region that was exacerbated by ankle joint movement and resolved with the improvement of the lower leg edema. Therefore, his symptoms were probably due to tarsal tunnel syndrome. The clinical manifestations and course of the disease, combined with the positive B19V-IgM antibody test results, led to a definitive diagnosis of B19V infection.

Conclusions

B19V infection in adults can mimic vasculitis. In the present case, the initial clinical presentation and laboratory results strongly suggested SVV; therefore, the patient was examined, while we considered MPA, particularly because of the potential for rapid progression of renal dysfunction. Vasculitis requires rapid diagnosis; however, mimics should be ruled out. Therefore, even in older patients, it is critical to consider the possibility of B19V infection, particularly during epidemic periods of the viral infection, and conduct interviews and tests for differentiation.