Pleural and pericardial effusions with fever and altered mental status: an atypical presentation of bartonellosis

Abstract

A male in his 60s presented to the emergency department (ED) with a 3-week history of fever and progressive confusion. Initial laboratory and radiographic workup was largely unremarkable except for moderate bilateral pleural effusions. The patient was admitted on broad-spectrum antibiotics and further workup for fever of unknown aetiology. The differential diagnosis was broadened to different zoonotic infections, and subsequent laboratory testing showed a markedly elevated Bartonella henselae IgG and Bartonella quintana IgG (1:4096 and 1:512, respectively) in addition to positive B. henselae IgM titre (>1:20). During hospitalisation, the patient became more hypoxic and was found to have enlarging pleural effusions as well as a new pericardial effusion. The patient was treated with intravenous then oral doxycycline 100 mg two times per day and oral rifampin 300 mg two times per day for 4 weeks with subsequent improvement in clinical status as well as both effusions. This case highlights a unique presentation of Bartonella and its rare manifestation of pleural and pericardial effusions.

Background

Bartonellosis refers to a group of infectious diseases caused by Bartonella, a gram-negative coccobacillus with tropism for endothelial cells. Bartonella henselae, quintana and bacilliformis are responsible for the majority of human diseases.^{1 2} The most common symptoms of B. henselae and B. quintana present 7 to 10 days after inoculation and include cutaneous rash, localised lymphadenopathy, fever and malaise.¹ With disease progression, ocular, neurological, pulmonary and cardiac manifestations have been documented.^3–6 Although generally a self-limiting disease, given the potential for multiorgan morbidity, early diagnosis and treatment are paramount.

This case highlights the insidious onset of Bartonella infection and the only documented simultaneous pericardial and pleural effusions in an immunocompetent adult. Our patient presented with several confounding factors and atypical disease presentation that placed bartonellosis lower on the differential. We hope this case highlights a unique disease progression and manifestation of bartonellosis that emphasise the importance of maintaining an open differential to avoid confirmation bias.

Case presentation

A male in his 60s with a history of gastro-oesophageal reflux disease and hypertension presented to the emergency department (ED) with a 3-week history of fever and progressive confusion. Vital signs in the ED included a temperature of 37.7°C, tachypnoea to 25 breaths per minute and hypertension to the 181/99 mm Hg. The patient was oriented only to self and unable to speak in full sentences. The remainder of physical exam revealed painful left axillary and inguinal lymphadenopathy, and superficial abrasions on left forearm most consistent with cat scratches. The patient was given 1 L of normal saline in ED and started on intravenous cefepime 2 g, intravenous vancomycin 2 g and intravenous doxycycline 100 mg empirically for infection of unknown aetiology.

Investigations

The primary ED workup was directed towards meningitis or encephalitis. Initial labs revealed mild hyponatraemia to 134 mmol/L and transaminitis of alanine aminotransferase (ALT) to 51 U/L, but otherwise normal metabolic panel and complete blood count (table 1). Chest radiograph revealed trace left-sided pleural effusion. CT and MRI of head did not show any acute intracranial abnormalities. Primary infectious workup included blood cultures, Rickettsia (Rocky Mountain Spotted Fever (RMSF)), Ehrlichia and Lyme disease serology, which had pending results on admission. Lumbar puncture was attempted several times but was unsuccessful.

Table 1.

Basic haematological workup including complete cell count and comprehensive metabolic panel

	Day 0	Day 2	Day 4	Day 6	Day 8	Day 10
WBC (109 /L)	8.9	10.9	12.6	10.4	8.5	9.2
RBC (1012 /L)	4.9	4.9	5.3	4.6	4.6	4.7
HGB (g/dL)	15.7	15.7	17.1	14.8	14.5	14.8
HCT (%)	45.0	45.1	49.5	43.2	42.8	43.6
MCV (fL)	91.9	92.0	92.7	92.6	92.6	92.7
MCH (pg)	32.1	32.1	32.1	31.8	31.4	31.6
MCHC (g/dL)	34.9	34.9	34.6	34.4	33.9	34.1
RDW (%)	12.5	12.9	13.3	13.0	12.9	13.1
Platelet (109 /L)	315.0	330.0	381.0	386.0	367.0	385.0
Smear review					Burr cells
Sodium (mmol/L)	134.0	137.0	137.0	137.0	134.0	135.0
Potassium (mmol/L)	Haemolysed	4.0	3.9	3.5	3.8	4.1
Chloride (mmol/L)	103.0	104.0	103.0	101.0	101.0	100.0
CO2 (mmol/L)	26.0	23.3	28.0	30.7	27.0	29.4
BUN (mg/dL)	13.0	12.0	18.0	17.0	15.0	16.0
Creatinine (mg/dL)	1.0	0.8	0.8	0.8	0.7	0.7
EGFR (mL/min/1.73m2)	82.0	>90.0	>90.0	>90.0	>90.0	>90.0
Anion gap (mmol/L)	5.0	10.0	6.0	5.0	6.0	6.0
Glucose (mg/dL)	185.0	125.0	122.0	118.0	103.0	102.0
Calcium (mg/dL)	8.9	8.1	8.3	8.1	8.5	8.5
Albumin (g/dL)	3.4	2.8	2.7	2.8	3.1	3.2
AST (U/L)	Haemolysed	23.0	18.0	34.0	77.0	66.0
ALT (U/L)	51.0	46.0	32.0	66.0	153.0	205.0
Alk Phos (U/L)	68.0	67.0	59.0	58.0	66.0	67.0

Alk Phos, Alkaline Phosphatase; ALT, Alanine Transaminase; AST, Aspartate Aminotransferase; BUN, Blood Urea Nitrogen; CO2, Carbon Dioxide; EGFR, Estimated Glomerular Filtration Rate; HCT, Hematocrit; HGB, Hemoglobin; MCH, Mean Corpuscular Hemoglobin; MCHC, Mean Corpuscular Hemoglobin Concentration; MCV, Mean Corpuscular Volume; RBC, Red Blood Cell; RDW, Red Cell Distribution Width; WBC, White Blood Cell.

Given persistent fevers and worsening encephalopathy on hospital day 1, lumbar puncture was successfully reattempted which resulted in normal cell counts, culture and viral studies (table 2). Despite normal cerebrospinal fluid (CSF) studies, this patient’s diminished level of consciousness was presumed to be secondary to encephalopathy. Testing for sexually transmitted infections, serum EBV, zoonotic infections (Q Fever, Bartonella, Leptospira, Brucella, Tularemia), fungal studies, Toxoplasma gondii, Legionella urinary antigen and Quantiferon Tuberculosis Gold Plus were also included. RMSF IgG (1:128), Ehrlichia IgG (1:512), EBV serology and T. gondii IgG antibody were positive, while Bartonella titres were pending (table 3).

Table 2.

Cerebrospinal fluid (CSF) results on hospital day 2

	Result
CSF colour	Colourless
Appearance, CSF	Clear
Red Blood Cells (109 /L)	32 (h)
Nucleated cells (109 /L)	2
Neutrophils (%)	3.1
Mono/macrophage (%)	38.5
Lymphs (%)	58.5
#Cells counted for diff	65
Protein (19–65 mg/dL)	57
Glucose (48–79 mg/dL)	69

CSF, Cerebrospinal Fluid.

Table 3.

Complete list of serum tests for potential infectious pathogens

Laboratory test	Reference range & units	Result
Henselae IgG	<1:128 titre	1:4096
Henselae IgM	<1:20 titre	≥1:20
Quintana IgG	<1:128 titre	1:512
Quintana IgM	<1:20 titre	<1:20
Brucella IgG	Negative	Negative
Brucella IgM	Negative	Negative
Chlamydia trachomatis, NAA	Negative	Negative
Gonorrhoeae NAA	Negative	Negative
Legionella, urinary antigen	Negative	Negative
Leptospira Ab	Negative	Negative
Q fever IgG, PH1	<1:16	<1:16
Quantiferon TB gold plus interpretation	Negative	Negative
EBV IgG	Negative	Positive
EBV IgM	Negative	Positive
EBV nuclear IgG Ab	Negative	Positive
EBV PCR, qualitative not blood	Negative	Negative
Hep A IgM	Nonreactive	Nonreactive
Hep B surface Ag	Nonreactive	Nonreactive
Hep B core IgM	Nonreactive	Nonreactive
Hepatitis C Ab	Nonreactive	Nonreactive
Histoplasma Ag, serum	Ng/ml	None detected
Coccidioides Ab	Negative	Negative
Coccidioides IgG	Negative	Negative
Coccidioides IgM	Negative	Negative
Blastomyces Ab	Negative	Negative
Histoplasma Ab mycelial CF	Negative	Negative
Histoplasma Ab yeast CF	Negative	Negative
Histoplasma Ab, immunodiffusion	Negative	Negative
Aspergillus fumigatus IgG	≤102 mg/L	8.1
Toxoplasma gondii IgG	Negative	Positive
Toxoplasma IgM	Negative	Negative
Ehrlichia IgG IFA	<1:64	1:512 (h)
RMSF IgG IFA	<1:64	1:128 (h)
RPR	Nonreactive	Nonreactive
Bordetella parapertussis	Not detected	Not detected
Mycoplasma pneumoniae	Not detected	Not detected
Chlamydophila (chlamydia) pneumoniae	Not detected	Not detected
Lyme Ab (serology)	Negative	Negative

Ab, Antibody; Ag, Antigen; CF, Complement Fixation; EBV, Epstein-Barr Virus; Hep A, Hepatitis A; Hep B, Hepatitis B; IFA, Indirect Fluorescent Antibody Test; IgG, Immunoglobulin G; IgM, Immunoglobulin M; NAA, Nucleic Acid Amplification; PCR, Polymerase Chain Reaction; RMSF, Rocky Mountain Spotted Fever; RPR, Rapid Plasma Reagin; TB, Tuberculosis.

On day 2, he developed a new oxygen requirement and atrial fibrillation prompting a transthoracic echocardiogram which showed an isolated moderate posterior pericardial effusion without valvular vegetations (figure 1). Repeat chest X-ray demonstrated mild to moderate bilateral pleural effusions (figure 2). On day 4, Bartonella antibody panel revealed markedly elevated B. henselae IgG and B. quintana IgG (1:4096 and 1:512, respectively) in addition to positive B. henselae IgM titre (>1:20) (table 2). Subsequently, oral rifampin 300 mg two times per day was added to doxycycline 100 mg two times per day, and given the marked titres, transoesophageal echocardiogram (TOE) was ordered to assess for endocarditis which showed the absence of vegetations and resolution of pericardial effusion. The team considered thoracentesis for pleural effusions, but due to decreased size (figure 3) after antibiotic therapy as stated above, risks outweighed the benefits. Of note, patient developed left conjunctivitis with pain on day 5. Ophthalmology deemed low suspicion for Parinaud’s Oculoglandular Disease or Neuroretinitis, and symptoms were attributed to pterygium, unrelated to his bartonellosis.

Figure 1.

Echocardiogram on hospital day 2. These images highlight the posterior pericardial effusion. Note the absence of valvular vegetations.

Figure 2.

Chest X-ray on hospital day 2 with mild pulmonary oedema and left greater than right effusion.

Figure 3.

Chest X-ray on hospital day 4 with left greater than right pleural effusions, and left mid and lower lung zone airspace opacities most consistent with atelectasis. Improved aeration of the right lung and improvement in previously seen vascular congestion.

Differential diagnosis

The patient’s avid outdoor lifestyle and exposure to various pathogens from fresh water, ticks, mosquitoes and to his cat scratches made pathogen identification from an exposure history challenging. His history and initial clinical presentation were concerning for tick-borne diseases (ie, RMSF and Ehrlichiosis), as well as other zoonotic infections that may cause fever and lymphadenopathy such as tuleremia and Yersinia pestis. Viral and bacterial meningitis were also considered but patient’s benign CSF made this less likely. The lack of RMSF rash was atypical and prompted additional infectious workup as indicated in the investigation section. However, RMSF infection can present without a rash,⁷ and in the setting of patient’s high exposure risk and other constellation of findings seen in RMSF, it was still considered the most likely diagnosis. Positive serological results for RMSF and Ehrlichia and patient’s clinical improvement to doxycycline seemed to validate the diagnosis and exclude viral aetiologies.

It was not until the patient had fever recurrence, worsening encephalopathy and hypoxia, and conjunctivitis that the team reassessed his diagnosis. A diagnosis of bartonellosis was suggested as the most likely aetiology once titres resulted. The clinical picture, along with positive IgM and IgG titres, strongly suggested acute infection rather than previous exposure. Ehrlichia and RMSF IgG positivity were likely due to prior infection or cross-reactivity rather than concurrent infection. Since the CSF studies were unremarkable, we attributed the encephalopathy to critical illness rather than encephalitis or some other primary neurological aetiology. EBV viral capsid antigen (VCA) IgM was positive, but EBV viral load (VL) was negative and EBV VCA IgG and Nuclear Ag IgG were positive as well, indicating prior (not active) infection.

Treatment

This patient initially received broad-spectrum antimicrobial coverage with intravenous cefepime 2 g, intravenous vancomycin 2000 mg and intravenous doxycycline 100 mg. Vancomycin and cefepime were discontinued after 2 days due to positive IgG antibodies to RMSF and Ehrlichia. Monotherapy with doxycycline 100 mg two times per day was maintained until B. henselae IgG and IgM antibodies came back positive on day 4, at which time oral rifampin 300 mg two times per day was added.

Outcome and follow-up

This patient was discharged on hospital day 11 with oral rifampin 300 mg two times per day and doxycycline 100 mg two times per day to complete a 4-week course. At follow-up 2 weeks after discharge, the patient reported improving mental status and memory and resolution of all other symptoms. Subsequent follow-up at 4 weeks after discharge to assess clinical status after discontinuing antibiotic therapy was uneventful; the patient reported no new symptoms suggestive of residual disease or recurrence.

Discussion

Our case is the first documented presentation of Bartonella with both pericardial and pleural effusion in an immunocompetent adult.

There are only five cases of isolated pericardial effusion associated with bartonellosis seen on echocardiogram.^{5 8–11} Patients with a pericardial effusion reported prodromal fever, fatigue and flu-like symptoms. In two cases, patients were found to have pericardial effusions after readmission with persistent or worsening fever, dyspnoea and flu-like symptoms at which time a subsequent diagnosis of bartonellosis was made.^{5 8} All patients exhibited improvement or resolution of pericardial effusion after antibiotic therapy targeting Bartonella was initiated.

Similarly, pulmonary manifestations of bartonellosis are uncommon, especially pleural effusions.^12–14 Our patient presented with a trace left-sided pleural effusion that progressively advanced to mild to moderate bilateral pleural effusions that started to resolve within several days after proper antibiotic administration. In the absence of thoracentesis, we cannot definitively attribute a causal relationship between the pleural effusion and Bartonella. However, given the improvement after antibiotic administration, and isolated effusions without other pulmonary manifestations, a causal relationship is highly likely.

Bartonella species are known to invade erythrocytes and endothelial cells and increase host susceptibility to additional infections by altering the immune system.¹ Certain Bartonella bacterial proteins inhibit immune function by reducing phagocyte migration, antigen presentation, complement and B-cell activation.¹⁵ It is likely that the pericardial and pleural effusions were signs of haematological spread of Bartonella beyond the primary infection site to cardiac and pleural parenchyma. However, given the immunomodulatory effects of Bartonella, these effusions could also represent opportunistic, superimposed bacterial or viral infections.

Although guidelines recommend doxycycline in complicated bartonellosis in combination with gentamicin (preferred with endocarditis) or rifampin (preferred with retinitis or encephalopathy), there is no definitive curative regimen.¹⁶ In addition to ours, dual antibiotic therapy was used in two cases,^{5 8} while two other cases found success with either azithromycin or clarithromycin alone.^{9 10}

Although Bartonella infection is typically a mild and self-limiting disease, this case report adds to existing evidence pertaining to multiorgan manifestations of bartonellosis requiring hospitalisation. Diagnostic clarity is important in these cases as targeted treatment is required for protection against end-organ damage and resolution of disease. Additionally, while bartonellosis is most commonly a disease of children, young adults and immunocompromised individuals, it is important to consider in the differential diagnosis of prolonged fever of unknown origin or multisystem diseases in immunocompetent adult populations.¹⁷ Along with considering this in the differential, it is important to examine the interdigital spaces, skin creases and scalp of the patient to increase the chance of finding the primary inoculation lesion. Bartonella infection historically was thought to be from cat bites or scratches but can be transmitted from arthropod vectors such as ticks, lice, chiggers and mosquitoes.¹

While bartonellosis was the most likely aetiology in this case, the patient could have had another zoonotic infection that was responsive to tetracyclines. Of those causing fever and lymphadenopathy, Yersinia pestis usually causes painful lymphadenopathy,¹⁸ which was not present in this case and no ulcer was noted that typically occurs at the site of inoculation in tularemia.¹⁹

The positive IgG titre can represent prior infection or cross-reactivity with other bacterial antibodies (Brucella spp, C. psittaci and C. burnettii).²⁰ Additionally, seroprevalence of B. henselae in healthy individuals may be around 4%.²¹ However, the clinical picture in this case with the positive IgM titre favoured acute infection. While PCR and blood culturing test exist for Barontella, positive serology has a specificity of 90% to 100% and a positive predictive value of nearly 92%.¹ Bartonella is very difficult to culture on blood agar as it can take weeks to isolate the bacteria and grow subcultures making the process time consuming and expensive.¹ PCR testing could have further supported the diagnosis but given the improvements seen in the patient with appropriate treatment for bartonella, it would not have changed management and further testing was deferred in this case. PCR testing can be useful in cases of culture-negative endocarditis or lymphadenitis of unclear aetiology.²²

Patient’s perspective.

Excerpt taken from phone conversation with the patient 6 months after discharge:

I do not remember anything after my nephew calling 911. I remember the rescue squad picking me up at the house for just a short while and then I have no memories. For the first 8 days of the hospital stay, I remember little to none. I tell people I was in a different world, and I was having nightmares about it. I was dreaming and it felt like I was living it, it felt like I was dying and being brought back to life. I remember the last 2 days of the hospital stay. I was really pleased with the patient care I was receiving. I had some really good doctors and nurses. It was a really scary experience for me. For the first little bit of time outside of the hospital, I was paranoid, particularly about my blood pressure. That went away in a couple of days. The only problem I am experiencing now is brain fog where my memory is not what it used to be and I have a pressure in my head. I don’t really know how to fully explain it. I think I am doing really well now. I hope this report is able to help people in the future.

Learning points.

• If patients have a change in their clinical symptoms after a diagnosis, especially one involving a zoonotic disease, maintaining a broad differential is critical to avoid complications and delayed treatment. This is crucial in potential zoonotic diseases as these pathogens may present as coinfections, often cross-react in serological testing and lead to infections in patients even without a clear exposure history.

• Bartonella should be considered in the differential diagnosis in patients presenting with altered mental status, fever and lymphadenopathy even with atypical symptoms, especially with exposure history.

• Consider Bartonella on your differential in a febrile patient with pleural and pericardial effusions.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).