Crescentic Glomerulonephritis and Portal Hypertension with Chronic Q Fever: A Case Report and Comprehensive Literature Review

Introduction

Q fever, an infectious zoonotic disease caused by the Gram-negative bacterium Coxiella burnetii, was once considered a rare and regionally restricted disease. However, recent years have seen significant advances in our understanding of this disease, which has spread widely in China and developing regions worldwide. People typically become infected by inhaling contaminated aerosols that can be generated from products of infected animals, mainly cattle, goats and sheep.¹ The clinical manifestations of Q fever can present as either an acute, self-limiting febrile illness or as a chronic disease, which may lead to complications such as vasculitis and endocarditis.²

However, there are only a limited number of reports addressing renal injury^3–7 or hepatic complications⁸ associated with the progression of the disease to its chronic stage. To our knowledge, this is the first case report documenting chronic Q fever with concurrent renal and hepatic involvement.

Case Presentation

A 70-year-old female patient who underwent bioprosthetic mitral and aortic valvular replacement because of degenerative heart valvular disease at the age of 68, presented with a six-month history of nightly low-grade fever. During the second month following the onset of fever, she experienced proteinuria and significant hematuria. Blood tests revealed significant pancytopenia. In the fourth month of fever duration, she exhibited oliguria, lower-leg edema and abdominal distension, accompanied by an elevation in serum creatinine up to 829μmol/L. She refrained from interacting with domesticated animals such as cattle, horses, sheep, and donkeys. Hemodialysis and renal biopsy were performed in the local hospital. Immunofluorescence revealed linear staining of IgG (2+), C3 (2+), IgG1 (2+) and IgG2 (2+) deposits along the glomerular capillary walls. In light microscopy, 13 out of 25 glomeruli exhibited cellular or cellular fibrous crescents. The glomeruli displayed with mesangial and endocapillary hypercellularity. Partial destruction of the Bowman capsule wall was accompanied by the formation of periglomerular granuloma. Electron microscopy demonstrated evidence consistent with tubular-interstitial nephropathy (Figure 1).

Figure 1 Kidney biopsy findings. (A) Periodic acid–Schiff (PAS) staining shows cellular crescent and periglomerular granuloma formation. (B) PAS, Black arrow shows a glomerulus with cellular crescent (involving above 50% of the glomerular circumference). Red arrow indicates protein and red cell cast in the renal tubules. (C) PAS, Acute tubular injury with cells vacuolar and granular degeneration in renal tubular epithelial, along with dilated renal tubules and diffuse exfoliation of the brush border. (D) Immunofluorescence revealed linear staining of IgG (2+) deposits along the glomerular capillary walls. Original magnification, ×400.

She received a course of glucocorticoid pulse therapy (250mg × 3d), followed by 30 mg of oral prednisolone daily, and underwent four sessions of plasma exchange. Despite this intensive treatment, the patient showed no response and was subsequently referred to a higher-level hospital for further management.

Examination of her distended abdomen revealed non-tender splenomegaly, with positive shifting dullness noted upon observation. Blood testing shows a white blood cell count of 3.1×10⁹/L, hemoglobin level of 82 g/L and platelet count of 59×10⁹/L. The patient tested negative for various autoantibodies, including anti–double-stranded DNA antibodies, ANCA, anti GBM antibodies including anti-α1-5, anti-Laminin-521 and anti-heparan sulfate proteoglycan 2 (HSPG2) antibodies, autoimmune liver disease antibodies, antiphospholipid antibodies and platelet antibodies. A comprehensive screening for the infection source and pathogens was conducted, including blood cultures, CMV/EBV-DNA and antibody tests, as well as G and GM tests for fungal infections. The results did not reveal a clear pathogen or infection source. Testing for EBV-DNA (serum), brucellosis, as well as viral hepatitis was negative. And she did test positive for cryoglobulins and human heparin-associated antibody. Additionally, C3 and C4 levels were found to be decreased (Table 1).

Table 1 Baseline and Follow-Up Manifestation of the Case

The abdominal ultrasound revealed dilatation of the portal vein, splenomegaly, and extensive accumulation of ascitic fluid. Echocardiography showed a slightly elevated pulmonary artery systolic pressure (38.8mmHg) and a mass on the surface of the left ventricular papillary muscle with potential vegetations, Positron emission tomography/computed tomography (PET/CT) demonstrated localized nodular wall thickening on the right side of the ascending aorta and increased glucose metabolism, indicative of a localized infection (Supplementary Figure 1). Furthermore, metagenomic next-generation sequencing (mNGS) detected Coxiella burnetii (12,570 reads, 896 reads per million [RPM]) and human herpesvirus 4 (Epstein-Barr virus, 31 reads, 2.1 RPM) in the venous blood sample.

The interventional percutaneous liver biopsy revealed the presence of nodular regenerative hyperplasia of hepatocytes, indistinct branches of the portal vein, dilated sinusoids, and focal hepatic plate atrophy and disappearance in certain areas collectively contributing to the development of non-cirrhotic portal hypertension. Additionally, chronic intrahepatic cholestasis was observed in the liver (Figure 2). Coxiella burnetii (78 RPM) was also found in liver tissue but not observed in renal tissue.

Figure 2 Liver biopsy of patient shows non-cirrhotic portal hypertension. (A) Reticulin ×200, Nodular regenerative hyperplasia of hepatocytes. (B) H&E ×400, No corresponding branches of the portal vein in the portal triads (PT); dilatation and congestion of the hepatic sinuses, accompanied by atrophy and disappearance of the hepatic plates in zones 2–3. (C) H&E ×200, Significant dilation of hepatic sinuses and atrophy of hepatic plates in some regions. (D) H&E ×400, Hepatic plates remain intact in some regions, with mild thickening and inflammation of the central venous wall, accompanied by inflammatory cell infiltration within the surrounding hepatic sinuses.

Finally, the patient was diagnosed with chronic Q fever, ascending aorta infection leading to crescentic glomerulonephritis and non-cirrhotic portal hypertension resulting in splenomegaly and hypersplenism.

She was initiated on a treatment regimen of doxycycline and hydroxychloroquine, with a reduction in prednisolone to 15 mg. This led to a significant reduction in ascites. After two months of treatment, the frequency of hemodialysis was successfully reduced to once a week. The serum creatinine level decreased to 345 μmol/L before each dialysis session. Her platelet count remained stable at 65×10⁹/L (Table 1).

Discussion

Despite the global prevalence of Q fever, the rarity of both acute and chronic cases with negative blood cultures in China results in a notably high rate of clinical misdiagnosis and missed diagnoses.⁹ Traditionally, the diagnosis of Q fever is confirmed through serological testing, which detects elevated levels of Phase I and Phase II antibodies against Coxiella burnetii. It is generally believed that the titer of antiphase II IgG ≥220 and/or IgM ≥50 is of great significance for diagnosing primary Q fever infection. While the elevated IgG titers of ≥1:800 of antiphase I antibodies are related to chronic Q fever.¹⁰ However, they were not widely used in clinical practice in China. We conducted a comprehensive literature review on previous cases of chronic Q fever with renal or hepatic involvement (Table 2, Supplementary Tables 1,2 and Supplementary literature review methods). To the best of our knowledge, the present study on chronic Q fever represents the first reported case of crescentic glomerulonephritis with periglomerular granuloma observed in renal biopsy, along with noncirrhotic portal hypertension.

Table 2 Chronic Q Fever Associated with Glomerulonephritis Confirmed by Kidney Biopsy

A summary of previously reported cases of renal biopsy-proven renal disease in chronic Q fever is presented in Table 2 and Supplementary Table 1. Most (11 out of 13) patients had a history of cardiac disease or cardiac surgery and presented with an ill-defined fever. Serology was used for diagnostic purposes in all patients, with one patient in 2018 additionally confirmed through real-time polymerase chain reaction (PCR). The most common histopathological pattern observed was proliferative glomerulonephritis with or without crescents. Six patients succumbed to their illness, primarily during the 1960s or 1970s. Regarding specific kidney biopsy results, mesangial and endocapillary proliferation was identified as the predominant renal change in light microscopy. Positive staining was primarily detected for IgM and C3. Granulomas, a distinctive pathological alteration resulting from infection, were absent in renal tissues of all cases but were detected in our patient, further suggesting that the lesion in our patient may have originated from an infection. The pathogenesis of crescentic nephritis associated with Coxiella burnetii remains elusive. Nevertheless, even in the absence of detected Coxiella burnetii sequences in renal tissue using mNGS or observations under light microscopy, the pathological findings in the kidneys strongly imply that infection may significantly contribute to the renal damage in this patient. This, in turn, likely triggers immune-mediated inflammatory responses in the kidneys.

Liver involvement is relatively common in acute Q fever. Although we detected Coxiella burnetii in the liver specimen using mNGS, granulomas were not identified in the liver tissue. This may be attributed to the chronic nature of the liver changes, with a reduction in granulomas and an increase in fibrosis. This point is supported by a case reported in 1988, wherein the patient underwent four liver biopsies within an 11-month period. Granulomatous lesions gradually diminished over time, resulting in minimal fibrotic changes.⁸ However, the mechanism underlying non-cirrhotic portal hypertension caused by Q fever remains unclear. In this case, the discovery of hepatic portal vein reflux obstruction, subsequent disappearance, along with a positive mNGS for Coxiella burnetii support the point that non-sclerotic portal hypertension in the liver could be attributed to Coxiella-induced venous inflammation. However, the absence of I/II phase antibody in China precludes obtaining definitive evidence from antibody titration levels.

And the comprehensive diagnostic testing methods such as microbial culture, serological assays, and PCR-based nucleic acid detection are not widely available in most medical institutions including tertiary hospitals in China. In contrast, mNGS, a revolutionary technology that is more sensitive than PCR technology, has successfully diagnosed a number of acute and chronic Q fever patients in China,^11–13 as well as identified the first confirmed epidemic of Q fever in a contemporary city in China.¹⁴

Organ damage caused by Q fever is not uncommon; however, due to disparities in healthcare standards across different countries and regions, many clinical experts remain unfamiliar with this disease.¹⁵ To mitigate the risk of kidney, liver, and cardiovascular complications associated with Q fever, it is essential to promote the widespread use of Q fever antibody testing kits and molecular diagnostics. These measures are crucial for preventing severe Q fever-related illnesses and ensuring that patients receive timely treatment.

Conclusions

We report a patient diagnosed with chronic Q fever and highlights a rare etiology of non-cirrhotic portal hypertension combined with crescentic glomerulonephritis contributing valuable insights to the limited understanding of kidney and liver diseases related to Q fever. Technologies including mNGS and PET/CT have been employed to identifying the Coxiella burnetii infection. And a prompt and appropriate treatment prevented further deterioration of renal and hepatic function.