Initial misdiagnosis to a revised diagnosis of pulmonary paragonimiasis with elevated serum immunoglobulin G4 concentrations: a case report

Abstract

An elevation in serum immunoglobulin (Ig) G4 concentrations at only one time point is not a definitive diagnostic marker for IgG4-related diseases. We report two cases of pulmonary paragonimiasis with elevated serum IgG4 concentrations. Patient 1 was a woman in her late 40s with cough and dyspnea for 1 week. Patient 2 was a woman in her late 60s with a cough, bloody sputum, chest pain, and wheezing for over 1 month. Patient 1 had eosinophilia, high IgE, IgG, and IgG4 concentrations, right pleural effusion, and lung lesions, resembling tuberculosis. Patient 2 had cavitary lung lesions, pleural involvement, and eosinophilia, and high IgE, IgG, and IgG4 concentrations, with a history of eating raw river crabs. Both patients tested positive for Paragonimus antibodies. Patient 1 received 2 months of anti-parasitic treatment, while Patient 2 had 1 week of treatment. Patient 2 showed improvement and was discharged with normalized Ig concentrations. Increased serum IgG4 concentrations, in conjunction with elevated concentrations of IgG, IgE and eosinophil counts, and a history of travel or residence in areas endemic for paragonimiasis, can be used to distinguish pulmonary paragonimiasis from other etiologies of pneumonia.

Introduction

Serum immunoglobulin G4 (IgG4) concentrations have been widely used for the screening and diagnosis of IgG4-related disease (IgG4-RD). Elevated serum IgG4 concentrations and mass lesions are the most common clinical manifestations of IgG4-RD.^1–3 Previous studies^4–6 have reported an elevation in serum IgG4 concentrations in multicentric Castleman disease, allergic disease, eosinophilic granulomatous with polyangiitis (Churg–Strauss syndrome), sarcoidosis, and many infections and inflammation. Many misdiagnosed cases associated with elevated serum IgG4 concentrations occur in the differential diagnosis of autoimmune disease ⁶ and neoplastic disease. However, misdiagnosis in parasitic diseases is rarely reported. We report two cases of pulmonary paragonimiasis with elevated serum IgG4 concentrations. These two cases were misdiagnosed with IgG4-RD, tuberculosis, or eosinophilia, but eventually received a revised diagnosis of pulmonary paragonimiasis.

Case presentation

This study was carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and the report followed the CARE guidelines. ⁷ Ethics approval of this study was obtained from Southern Central Hospital of Yunnan Province (The First People’s Hospital of Honghe State; No. HY2022LLSC-157). Informed verbal consent was obtained from the two patients. The patients’ details were de-identified.

Case 1

The patient was a woman in her late 40s who was residing in the mountainous region in Yunnan, China. She presented to the Respiratory and Critical Care Medicine Department of our hospital on 10 December 2021 with the complaints of a cough and dyspnea for 1 week. A chest computed tomography (CT) scan performed at an another facility on 9 December 2021 showed a large right-sided pleural effusion with an infectious focus in the right middle lobe. She received an intramuscular injection (details not provided) at the other facility, leading to some relief of the cough symptoms, but dyspnea persisted. She self-described normal urinary and bowel habits, but noted a weight loss of approximately 3 kg since the onset of her illness. She denied a history of hypertension, diabetes mellitus, hepatitis, tuberculosis, or typhoid fever. A routine blood examination, chest CT scan, and chest ultrasound were performed on 10 December 2021. She showed an increase in the percentage of eosinophils (24.1%) and had elevated serum immunoglobulin (Ig) E (172.60 g/L), IgG (20.80 g/L), and IgG4 (11.33 g/L) concentrations to varying degrees (Table S1). Liver function parameters including globulin were mildly elevated (Table S2). A large right-sided pleural effusion and multiple inflammatory lesions in various lung lobes were observed (Figure 1(a), (b)). Pulmonary tuberculosis was considered a likely possibility. The patient underwent anti-tuberculosis treatment with isoniazid following a right-sided pleural tap with placement of a drainage catheter. Fluid from the drainage was sent to a laboratory for acid-fast staining, tuberculosis mycobacterial culture testing, a cytological examination, tuberculosis mycobacterial DNA testing, and tuberculosis infection T-cell testing. All of these tests yielded negative results. A routine examination of this fluid showed the following results: Rivalta’s test, 3+ positive; white blood cell count, 7220 × 10⁶/L; red blood cell count, 3500 × 10⁶/L; a few neutrophils; and lymphocytes were observed. The patient was provided an intravenous infusion injection of the fixed-dose combination of isoniazid (0.3 g) and 0.9% sodium chloride intravenous solution (100 mL), each day for 5 days. After 5 days of anti-tuberculosis treatment, the patient experienced a slight improvement in her symptoms and signs. However, there were no considerable changes in the eosinophil count or serum IgE, IgG, IgG4 or globulin concentrations. A follow-up chest CT showed no remarkable differences compared with the pre-treatment scan.

Figure 1.

Chest computed tomography imaging in a patient (Case 1) with paragonimiasis. (a) Cross-sectional image using the mediastinal window and (b) cross-sectional image using the lung window.

The patient was subsequently transferred to the Infectious Disease Department with a differential diagnosis of tuberculous pleuritis, secondary pulmonary tuberculosis, or IgG4-RD. The Infectious Disease Department team considered factors, such as the patient’s medical history and residence in an endemic area for parasitic infections. The possibility of parasitic infection needed to be considered because of insufficient evidence for tuberculosis infection. Further inquiry into the patient’s lifestyle showed a history of drinking untreated stream water. The patient underwent serological testing for Paragonimus antibodies and fecal examination for parasitic eggs. The Paragonimus antibody test, using the enzyme-linked immunosorbent assay method, showed positive results, with an optical-density ratio of 0.779 (optical density critical value = 0.210), while no parasitic eggs were observed in the feces. The patient was ultimately diagnosed with Paragonimus infection. The eosinophil count and serum IgE, IgG, IgG4, and globulin concentrations showed varying degrees of a decrease 1 week after 3 consecutive days of anti-parasitic treatment with praziquantel (1.2 g three times daily). A follow-up CT scan after 2 months of anti-parasitic treatment showed a minimal amount of right-sided pleural effusion (Figure 2(a), (b)). Eosinophils and serum IgE, IgG, and globulin concentrations returned to normal, and IgG4 concentrations approached the normal range (Tables S1 and S2).

Figure 2.

Chest computed tomography imaging in Case 1 after treatment. (a) Cross-sectional image using the mediastinal window and (b) cross-sectional image using the lung window.

Case 2

The patient was a woman in her late 60s who was residing in a mountainous region in Yunnan, China. She was diagnosed at another facility on 22 February 2022 with pulmonary infection, eosinophilia, or leukemia. This diagnosis was based on a white blood cell count of 30.25 × 10⁹/L in a routine blood examination and increased myelocyte, metamyelocyte, and eosinophil counts in the following bone marrow aspiration. She showed no improvement, despite attempted antimicrobial treatment. On 1 March 2022, she was transferred to our hospital’s Department of Hematology and Oncology, with an admission diagnosis of leukemia, pulmonary infection, or chronic bronchitis. A bone marrow aspiration was conducted, and an increase in the eosinophilic count was observed, which suggested eosinophilia. The possibility of leukemia was ruled out clinically. Treatment with prednisone 40 mg once daily was initiated, resulting in some improvement in symptoms. The patient was discharged on prednisone 40 mg once daily, with a subsequent taper to 25 mg once daily.

On 23 April 2022, the patient’s condition worsened, with complaints of cough, productive sputum with blood, chest pain, and wheezing persisting for more than 1 month, leading to readmission. A CT scan upon readmission (Figure 3(a), (b)) showed multiple cavitary lung lesions, bilateral hydropneumothorax, and collapse of the lungs owing to the presence of air and fluid between the two layers of the pleura. Laboratory investigations, including tuberculosis DNA, acid-fast staining of sputum, and tuberculosis infection T-cell testing, showed negative results. Closed chest drainage was performed during the diagnostic process, and acid-fast staining and cytological examinations of pleural fluid showed no abnormalities. Liver and kidney function tests were normal, and other laboratory tests did not show any abnormalities. Eosinophils and serum IgE, IgG, and IgG4 concentrations were considerably elevated (Table S3).

Figure 3.

Chest computed tomography imaging in Case 2 at the time of admission. (a) Cross-sectional image using the lung window and (b) coronal view.

An infectious disease consultation was performed because of the patient’s residence in a parasitic endemic area. After further inquiry into her dietary history, we discovered that she ate raw river crabs. These findings combined with the laboratory results suggested paragonimiasis as a possible diagnosis. The Paragonimus antibody test, using the enzyme-linked immunosorbent assay (method, showed positive results, with an optical-density ratio of 0.936 (optical density critical value = 0.210). A positive Paragonimus antibody test result confirmed the revised diagnosis as paragonimiasis. The patient was treated with praziquantel for 3 consecutive days. The initial dose was 1.2 g three times daily, but she experienced nausea and vomiting, and the dose was reduced to 0.6 g three times daily. She was also treated with benzylpenicillin for controlling infection, bromhexine for sputum reduction, acid suppression for gastric protection, and supportive care. The patient’s condition improved 1 week after 3 days of treatment with praziquantel, leading to discharge. Post-discharge instructions included continued anthelminthic treatment with regular follow-up appointments.

Discussion

Tuberculosis and paragonimiasis can lead to lung involvement, including repeated hemoptysis and lung cavity formation. Collapse of the lungs owing to the presence of air and fluid between the two layers of the pleura was observed in case 2, but not case 1, because cavitary lung lesions and pneumothorax were found in case 2, but neither cavitary lung lesions nor pneumothorax was found in case 1. Both patients in this report were not correctly diagnosed on the basis of clinical symptoms and imaging examinations. Therefore, an inquiry regarding the patients’ residential location and dietary history is particularly important. If a patient has an exposure history of related epidemiological factors (e.g., previous tuberculosis infection or tuberculosis history, known or possible tuberculosis exposure, or living in an endemic area for tuberculosis), tuberculosis should be considered. ⁸ If Mycobacterium tuberculosis is isolated from bodily secretions or fluid (e.g., sputum, bronchoalveolar lavage, or pleural effusion culture) or tissue (pleural biopsy or lung biopsy), the patient can be diagnosed with tuberculosis. ⁹

Paragonimiasis is a zoonotic disease caused by a parasite. Although the species of Paragonimus was not examined in this study, a previous study reported that Paragonimus microrchis, P. heterotremus, P. proliferus, and P. skrjabini were isolated and identified in crabs at Yunnan. ¹⁰ Paragonimus usually infects the lungs of humans after the consumption of raw or undercooked streamed crabs or Cambaroides dauricus infected with lung fluke metacercaria. ¹¹ The two patients in this report lived in mountainous regions in Yunnan, China and had a history of exposure to an infectious source. Their eosinophil levels were considerably elevated and their serum IgE, IgG, IgG4 and globulin concentrations were elevated to varying degrees. Finally, they were diagnosed with pulmonary paragonimiasis according to their positive results in a Paragonimus antibody test. Paragonimus-specific IgG4 was not measured in either case, and the elevation in IgG4 concentrations may have been caused by production of polyclonal IgG4. Therefore, a Paragonimus-specific IgG4 subclass should be investigated in the future. A diagnosis without taking into consideration the residential location or dietary history could cause a missed diagnosis or misdiagnosis. Moderate to severe eosinophilia and positive parasite antibodies are helpful in the differential diagnosis of paragonimiasis.

Peripheral blood eosinophilia can result from a variety of diseases, such as allergies, infections, inflammation, and neoplastic diseases. Infectious causes of eosinophilia include worms, fungi, protozoa, bacteria, retrovirus (human immunodeficiency virus), human T-lymphocyte virus type 1, and scabies. Most of the acute bacterial and viral infections will not cause eosinophilia. Worm infection is the most common infectious cause of eosinophilia. ¹²

Serum globulin concentrations in our two patients were elevated, which is similar to the results of Detlefsen et al. ¹³ T-helper type 2 cells can contribute to production of IgG4 and IgE and induce an elevation in eosinophils. Among our patients, serum IgG4, IgE, and IgG concentrations and the eosinophil count in Case 1 decreased after anti-parasitic treatment and showed a strong association with the therapeutic intervention. This finding is consistent with a study by Hong et al. ¹⁴ who found that specific serum IgG and IgG4 antibody test results in patients severely infected with Clonorchis sinensis were positive. They found that positive rates of IgG and IgG4 antibody tests were directly correlated with the intensity of infection in patients, and specific serum IgG4 antibodies in patients disappeared within 6 months after treatment.

Antibodies specific to certain pathogens are in specific IgG subclasses. IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4. Antibodies binding to bacterial polysaccharide antigens (e.g., pneumococcal capsule antigen) are mainly IgG2 antibodies. ¹⁵ Antibodies binding to protein and viral antigens are mainly IgG1 and IgG3 antibodies.^16,17 The biological role of IgG4 is still not fully understood, but antibodies binding to chronic schistosomiasis and filariasis are mainly IgG4 antibodies, suggesting that IgG4 plays a role in the immune response against parasitic diseases.^18,19

Conclusion

Lesions found in our two patients occurred in the respiratory system. In patients with elevated IgG4 concentrations and elevated eosinophil levels, IgG and IgE testing may need to be performed with a parasite antibody test, while also considering the patient’s residential location and dietary history, to achieve a correct diagnosis.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251317980 - Supplemental material for Initial misdiagnosis to a revised diagnosis of pulmonary paragonimiasis with elevated serum immunoglobulin G4 concentrations: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605251317980 for Initial misdiagnosis to a revised diagnosis of pulmonary paragonimiasis with elevated serum immunoglobulin G4 concentrations: a case report by Pengyan Yin, Miaohui Duan, Lingyao Deng, Tianli Li, Xuan Huang, Raohong Fang, Hailong Li and Binliang Bai in Journal of International Medical Research