Peliosis

Peliosis is rare benign blood vessel condition characterized by multiple, randomly distributed, blood-filled and cyst-like cavities throughout the tissue of solid organs. Peliosis is a term derived from the Greek pelios, which means “dusky” or “purple,” referring to the color of the liver tissue with peliosis ¹⁾. Similar blood-filled spaces may be seen in the spleen (splenic peliosis), lymph nodes, and other organs including the bone marrow, lungs, pleura, kidneys, adrenal glands, stomach, and ileum ²⁾, ³⁾.

Peliosis was first described in the liver (peliosis hepatis) by Wagner in 1861, and was later named by Schoenland in 1916 ⁴⁾, ⁵⁾. Although the pathogenesis of peliosis is still unknown, several hypotheses have been studied. Some researchers reported that toxic or viral substances induce hepatocellular necrosis with a sinusoidal dilatation, while others proposed a congenital vascular malformation or an active vessel proliferation ⁶⁾.

Peliosis is generally understood to develop within organs of the mononuclear phagocytic system such as the liver, spleen, marrow, and lymph nodes of the abdomen ⁷⁾.

Preliminary evidence links the development of peliosis to angiogenesis (formation of new blood vessels) due to elevated levels of vascular endothelial growth factor (VEGF) ⁸⁾. VEGF is a fundamental regulator of physiologic angiogenesis. Elevated VEGF levels are known to be associated with tumor progression and poor outcomes in a number of cancers. A condition resembling peliosis has been demonstrated in mice with elevated VEGF levels, that were found to have massively dilated hepatic sinusoids and endothelial cell proliferation and apoptosis ⁹⁾. The experimental link to elevated VEGF levels, warrants investigation into the treatment of peliosis with anti-angiogenic factors ¹⁰⁾.

Peliosis hepatis

Peliosis hepatis also called “peliosis hepatitis” is rare benign blood vessel condition characterized by multiple, randomly distributed, blood-filled and cyst-like cavities throughout the liver ¹¹⁾, ¹²⁾, ¹³⁾, ¹⁴⁾, ¹⁵⁾. These blood-filled cavities communicate with the hepatic sinusoids and are associated with rupture of the reticulin framework ¹⁶⁾. The size of the cystic lesions may vary from 1 millimeter to several centimeters ¹⁷⁾. The cystic lesions are often irregularly shaped and in many cases are incompletely lined with endothelium ¹⁸⁾. Peliosis hepatis has been described as typically involving the entire liver ¹⁹⁾.

Peliosis mostly exists without symptoms (asymptomatic) being incidentally found on imaging or during an autopsy ²⁰⁾. However, with the progress of modern medical imaging technologies such as ultrasound, magnetic resonance imaging (MRI), FDG-PET (fluorodeoxyglucose positron emission tomography) or computed tomography (CT) scan, peliosis hepatis is now more frequently encountered in clinical practice ²¹⁾. Despite these various medical imaging modalities, imaging may be inadequate for establishing a clear diagnosis of peliosis ²²⁾, ²³⁾.

Peliosis hepatis can occur at any age. Although a fetal form exists, peliosis hepatis usually develops in adults without regard to sex ²⁴⁾.

The cause of peliosis hepatis can be related to drugs including anabolic steroids, oral contraceptives, corticosteroids, tamoxifen, diethylstilbestrol, azathioprine, 6-thioguanine, 6-mercaptopurine, and methotrexate; toxins such as polyvinyl chloride, arsenic, and thorium oxide; chronic wasting diseases (e.g., tuberculosis, leprosy, and various cancers, particularly hepatocellular carcinoma); liver and kidney transplantation; and Bartonella henselae and Bartonella quintana infection in AIDS so-called bacillary peliosis ²⁵⁾, ²⁶⁾, ²⁷⁾, ²⁸⁾, ²⁹⁾. In addition, several other conditions are described as associated with peliosis hepatis, including sprue (a disorder in which the intestines are unable to absorb nutrients from food), diabetes mellitus, necrotizing vasculitis, and blood disorders including multiple myeloma, aplastic anemia, Hodgkin disease, and myelofibrosis ³⁰⁾. Moreover, peliosis hepatis may develop after kidney or heart transplantation. In 20 to 50% of patients, no associated condition is identified ³¹⁾.

Peliosis hepatis is very difficult to diagnose. The diagnosis of peliosis hepatis is often missed or delayed because it is usually asymptomatic, and its radiologic appearance closely resembles a benign and malignant/pre-malignant lesions or multiple abscesses ³²⁾, ³³⁾. Radiological imaging shows a broad spectrum of appearances because of its dependence on the blood supply to the lesions. Laparoscopy is a useful examination to sporadically detect dark-blue or dark-red patchy patterns on the liver surface, which is a characteristic finding of peliosis hepatis ³⁴⁾. Pathological findings are considered the gold standard for the diagnosis of peliosis hepatis, being histologically characterized by blood-filled cavities. However, a case has been reported in which repeated biopsies were required to diagnose peliosis hepatis ³⁵⁾.

The correct diagnosis of peliosis hepatis is important because withdrawal of the offending drug or toxin can resolve the disease and prevent serious complications such as hepatic failure or death related to intraabdominal hemorrhage ³⁶⁾. Because of peliosis hepatis potential complications, surgical resection of the involved liver parenchyma should always be considered. In HIV-related peliosis hepatis caused by Bartonella henselae, clinical improvement has been documented with the use of antibiotics (i.e., erythromycin).

Figure 1. Peliosis hepatis

Footnotes: 51-year-old woman with history of benign ovarian tumor and incidentally discovered hepatic mass. On contrast-enhanced CT during hepatic arterial phase, lesion (arrow) shows marked homogeneous contrast enhancement.

[Source ³⁷⁾ ]

Figure 2. Peliosis hepatis liver biopsy specimen

Footnote: Liver biopsy specimen with hematoxylin and eosin staining at 45x magnification showing dilated vascular spaces (peliotic spaces) filled with red blood cells are surrounded by cords of hepatocytes. Note central area of pale myxoid stroma (arrow)

[Source ³⁸⁾ ]

Figure 3. Bacillary peliosis

Footnotes: 44-year-old man with AIDS and bacillary peliosis. Transverse contrast-enhanced CT image shows large ill-defined, hypoattenuating lesion (white arrow) with heterogeneous peripheral enhancement within left liver lobe. Smaller subcapsular hypoattenuating lesion (black arrow) with ring enhancement can also be seen in right liver lobe.

[Source ³⁹⁾ ]

Peliosis hepatis cause

The cause of peliosis hepatis can be related to drugs including anabolic steroids, oral contraceptives, corticosteroids, tamoxifen, diethylstilbestrol, azathioprine, 6-thioguanine, 6-mercaptopurine, and methotrexate; toxins such as polyvinyl chloride, arsenic, and thorium oxide; chronic wasting diseases (e.g., tuberculosis, leprosy); cancers, particularly hepatocellular carcinoma; liver and kidney transplantation; and Bartonella henselae and Bartonella quintana infection in AIDS so-called bacillary peliosis ⁴⁰⁾, ⁴¹⁾, ⁴²⁾, ⁴³⁾, ⁴⁴⁾. In addition, several other conditions are described as associated with peliosis hepatis, including sprue (a disorder in which the intestines are unable to absorb nutrients from food), diabetes mellitus, alcoholic liver disease, necrotizing vasculitis, and blood disorders including multiple myeloma, aplastic anemia, Hodgkin disease, and myelofibrosis ⁴⁵⁾, ⁴⁶⁾, ⁴⁷⁾, ⁴⁸⁾. Moreover, peliosis hepatis may develop after kidney or heart transplantation. In 20 to 50% of patients, no associated condition is identified ⁴⁹⁾.

Peliosis hepatis causes ⁵⁰⁾:

• Idiopathic: 20 to 50% of cases
• Toxins
  • arsenic
  • polyvinyl chloride (PVC)
  • thorium oxide
• Drugs
  • anabolic steroids
  • azathioprine
  • corticosteroids
  • diethylstilbestrol (DES)
  • immunoglobulin therapy
  • methotrexate
  • oral contraceptives
  • tamoxifen
  • 6-thioguanine (6-TG)
  • 6-mercaptopurine (6-MP)
• Chronic illness
  • malignancy, particularly hepatocellular carcinoma
  • tuberculosis (TB)
  • leprosy
  • celiac sprue
  • diabetes mellitus
  • necrotizing vasculitis
  • hematologic disorders: Hodgkin disease, multiple myeloma
• Infection in AIDS
  • bacillary peliosis caused by Bartonella henselae, Bartonella quintana and Rochalimaea henselae
• Kidney or heart transplantation

Peliosis hepatis pathophysiology

Peliosis hepatis pathogenesis remains poorly understood, with various investigators proposing that the primary event could be obstruction of hepatic outflow at the sinusoidal level, direct breakdown of sinusoidal borders, dilatation of the central vein of the hepatic lobule, or hepatocellular necrosis leading to cavity formation ⁵¹⁾. Lastly, post-sinusoidal obstruction from several conditions such as malignant invasion, autoimmune inflammation, and drug injury is also hypothesized to be an alternate mechanism in the formation of peliosis hepatis ⁵²⁾.

The anatomy of the sinusoidal capillaries is different than other capillary beds within the body. The fenestrations which are present within the liver allow for passes and filtration of larger molecules such as albumin ⁵³⁾. Epithelial damage can result from smoking, which can disrupt the architecture through the formation of free radicals. This damage, in turn, impairs vasodilation by inhibiting nitric oxide formation, which allows for normal physiologic relaxation of the arteries ⁵⁴⁾. Additionally, inflammation, whether it be autoimmune, direct trauma through surgical instrumentation, medication-induced, or invasion by malignancy, can result in the recruitment of inflammatory cytokines and cells, sometimes resulting in further epithelial damage ⁵⁵⁾. An alternate mechanism may be the depletion of glutathione, a critical regulatory molecule that assists in many biochemical detoxification reactions, which may disrupt the integrity of the epithelial wall and allow toxic metabolites to build up. However, through signal proteins such as vascular endothelial growth factor and others, re-endothelization can occur; thus, that is why using the absence of epithelial lining on imaging studies is not adequate to diagnose patients with peliosis hepatis, though it can raise the concern for it ⁵⁶⁾, ⁵⁷⁾.

Histologically, hepatic peliosis is characterized by multiple mottled blood-filled cyst-like spaces within the liver with associated sinusoidal dilatation ⁵⁸⁾, ⁵⁹⁾. These vary in size from <1 mm to several centimeters in diameter.

Macroscopically, the liver appears dark or even purple, and usually, the entire liver is involved to a greater or lesser degree. Focal lesions may demonstrate central areas of hemorrhage.

Peliosis hepatis symptoms

Peliosis hepatis varies from minimal asymptomatic lesions that is diagnosed incidentally on imaging or during an autopsy to massive lesions that may present with cholestasis, hepatic failure, or spontaneous rupture requiring liver transplantation ⁶⁰⁾, ⁶¹⁾. In some instances, enlarged liver (hepatomegaly), ascites (accumulation of fluid in the peritoneal cavity), portal hypertension, cholestasis, and hepatic failure may be present ⁶²⁾. Severe abdominal pain may result from rupture and intraperitoneal hemorrhage ⁶³⁾. In the case of bacillary peliosis, enlarged lymph node (lymphadenopathy) with Bartonella henselae and neurologic symptoms with Bartonella quintana are typical findings.

Peliosis hepatis complications

Peliosis hepatis complications may include:

• hepatic failure
• portal hypertension
• rupture and hemorrhage

There is no current consensus on whether patients with asymptomatic peliosis hepatis warrant routine imaging studies to monitor disease burden or progression. However, some experts believe annual or more frequent evaluation with ultrasound is adequate ⁶⁴⁾.

Although the incidence of intraperitoneal and intrahepatic hemorrhage do not seem to be common complications, the risk does exist ⁶⁵⁾. Thus surgical resection appears to assist in the avoidance of such complications, especially if imaging studies have demonstrated worsening of the cavitary lesions ⁶⁶⁾.

Peliosis hepatis diagnosis

Peliosis hepatis is very difficult to diagnose. The diagnosis of peliosis hepatis is often missed or delayed because it is usually asymptomatic, and its radiologic appearance closely resembles a benign and malignant/pre-malignant lesions or multiple abscesses ⁶⁷⁾, ⁶⁸⁾. Radiological imaging shows a broad spectrum of appearances because of its dependence on the blood supply to the lesions. In reality, the imaging findings of peliosis hepatis vary depending on the pathologic patterns of disease, various stages of the blood component of the lesions, and concomitant hepatic steatosis ⁶⁹⁾.

Laparoscopy is a useful examination to sporadically detect dark-blue or dark-red patchy patterns on the liver surface, which is a characteristic finding of peliosis hepatis ⁷⁰⁾. Pathological findings are considered the gold standard for the diagnosis of peliosis hepatis, being histologically characterized by blood-filled cavities. However, a case has been reported in which repeated biopsies were required to diagnose peliosis hepatis ⁷¹⁾.

Ultrasound findings

Conventional gray-scale sonography appearances are non-specific, usually demonstrating an irregular hypoechoic region/mass ⁷²⁾

Doppler studies can show evidence of both perinodular and intranodular vascularity ⁷³⁾. Recently, the use of a sonographic contrast agent (Levovist [Schering], a galactose and palmitic acid compound) has been shown to provide a “fast surge” central-echo enhancement in peliotic lesions ⁷⁴⁾.

CT findings

Peliosis lesions appearance on pre-contrast CT (unenhanced CT) is variable, depending on liver density, but is usually of multiple hypoattenuating lesions of variable size ⁷⁵⁾. Central hemorrhage may lead to areas of hyperattenuation and even dystrophic calcification ⁷⁶⁾. CT findings vary with the size of lesions, presence or absence of thrombus within the cavities, and presence of hemorrhage. In particular, peliosis lesions may be spontaneously hyperattenuating to liver parenchyma in certain patients (probably related to intralesional hemorrhage). In addition, if peliotic cavities are smaller than 1 cm in diameter, CT findings may be normal ⁷⁷⁾. Calcifications within peliosis lesions have also been described.

On contrast-enhanced CT, peliosis lesions typically show early globular enhancement and multiple small, central accumulations of contrast material during the arterial phase, with a centrifugal progression of enhancement during the portal venous phase ⁷⁸⁾. In addition, some lesions can also show areas of increased attenuation. Notably, larger cavities communicating with sinusoids display the same attenuation of blood vessels, whereas thrombosed cavities have the same appearance as nonenhancing nodules ⁷⁹⁾. More often, during the arterial phase of contrast enhancement, peliosis lesions typically show early globular enhancement (vessel-like enhancement) and multiple small accumulations of contrast material in the center of the lesions the so-called target sign ⁸⁰⁾. During the portal venous phase, a centrifugal progression of enhancement without a mass effect on hepatic vessels is usually observed ⁸¹⁾; however, a centripetal progression of enhancement can also be seen ⁸²⁾. On the delayed phase, late diffuse homogeneous hyperattenuation can also be seen in the phlebectatic type of peliosis hepatis because of the lack of hemorrhagic parenchymal necrosis ⁸³⁾. This accumulation of contrast material in the delayed phase can be useful in the differential diagnosis with other focal hepatic lesions that do not show blood pooling. In some instances, small (< 2 cm) peliotic lesions may also show hyperattenuation on both arterial and portal venous phase images.

MRI findings

On MRI, the signal intensities of peliosis lesions largely depend on the stage and the status of the blood components ⁸⁴⁾. On T1-weighted images, lesions are hypointense or heterogeneously hypointense if complicated by hemorrhage. On T2-weighted images, they are usually hyperintense compared to the liver parenchyma. Hemorrhagic parenchymal necrosis and thrombosed cavities manifest as non-enhancing areas. The differential diagnosis of peliosis hepatis may differ according to the actual imaging findings. On T2-weighted images, high signal together with early lesion enhancement can mimic hepatocellular carcinoma or hypervascular metastasis ⁸⁵⁾, while a bright T2-weighted signal and persistent delayed-phase CT or MRI may help distinguish peliosis hepatis.

Angiographic findings

On angiography, peliosis lesions appear as multiple vascular nodules (i.e., accumulations of contrast material) during the late arterial phase. The enhancement of peliotic lesions typically is more distinct during the parenchymal phase and persists during the portal venous phase ⁸⁶⁾.

Biopsy findings

A percutaneous needle biopsy can be used to obtain a specimen to further elucidate imaging findings and confirm the diagnosis. However, a percutaneous liver biopsy carries a risk of bleeding and hepatic hemangioma formation ⁸⁷⁾. Some authors claim that, due to the high risk of bleeding, an open biopsy is essential in order to realize the differential diagnosis under intraoperative ultrasound supervision ⁸⁸⁾, ⁸⁹⁾, ⁹⁰⁾, ⁹¹⁾, ⁹²⁾, ⁹³⁾.

The gross pathologic appearance of peliosis hepatis is that of multiple, irregularly shaped blood-filled hepatic cavities ⁹⁴⁾. The lesions typically involve the entire liver, but focal peliosis hepatis has been described. At microscopic examination, cystic dilated sinusoids filled with red blood cells and bound by cords of liver cells can be seen (see Figure 1).

Macroscopic examinations show that peliotic lesions in the cutting section present hemorrhagic cyst cavities of various sizes (from < 1 mm to several centimeters) with features of “Swiss cheese”⁹⁵⁾, ⁹⁶⁾. From the histopathologic point of view, the differential diagnosis is used in order to diversify the sinusoids’ dilatation from Budd-Chiari syndrome, which determines a venous congestion of the liver due to a vascular occlusion ⁹⁷⁾, ⁹⁸⁾, ⁹⁹⁾.

Pathologists originally classified peliotic lesions by the presence or absence of endothelium (inner cellular lining of the blood vessels) ¹⁰⁰⁾. However, even though the blood-filled cavities do not always have endothelial lining , it has been observed that reendothelialization occurs rapidly ¹⁰¹⁾, ¹⁰²⁾, ¹⁰³⁾. Therefore, the continuity or rupture of the endothelial lining of hepatic sinusoids is not a reliable criterion to define peliosis hepatis ¹⁰⁴⁾. To distinguish peliosis hepatis from hepatic sinusoidal dilatation, lesions should show evidence of rupture of the reticulin fibers that support the hepatocytes and sinusoids ¹⁰⁵⁾. This rupture may follow the intrinsic weakness of the fibers of the endothelial wall (peliosis hepatis of the phlebectatic type) or may be associated with focal hepatocyte necrosis (peliosis hepatis of the parenchymal type) ¹⁰⁶⁾.

Yanoff et al ¹⁰⁷⁾ described microscopically two different types of peliosis hepatis:

• “parenchymal peliosis,” which consists of irregular cavities that are surrounded neither by the sinusoidal cells nor by fibrous tissue, and
• “peliosis flebectasica” which is characterized by spherical regular cavities coated by endothelium and/or fibrosis ¹⁰⁸⁾, ¹⁰⁹⁾, ¹¹⁰⁾

Peliotic lesions in bacillary peliosis contain clumps of organisms (i.e., Bartonella henselae and Bartonella quintana) that stain with the Warthin-Starry technique ¹¹¹⁾. Patients with bacillary peliosis often have peliosis of the spleen and lymph nodes and cutaneous angiomatous lesions ¹¹²⁾.

Peliosis hepatis differential diagnosis

• Hepatic adenoma: Similar to peliosis, hepatic adenoma might also be associated with the long-term use of estrogens. In the case of diffuse peliosis hepatis, the differential diagnosis is relatively easy. In addition, the presence of fat in some adenomas is a useful sign to make a differential diagnosis. In certain instances, however, focal peliosis can be difficult to differentiate from adenomas. In these patients, biopsy is often required to reach a definitive diagnosis.
• Cavernous hemangioma: The typical enhancement pattern of hemangiomas (i.e., globular discontinuous contrast enhancement tends to be centripetal (periphery first) rather than centrifugal (center first)) is opposite of peliosis hepatis, and therefore differential diagnosis can be achieved in most patients. In addition, hemangiomas may be rather large lesions with a mass effect on the hepatic vessels, whereas peliotic lesions usually show no mass effect on hepatic vessels.
• Hepatocellular carcinoma (liver cancer): Hepatocellular carcinoma is usually hyperattenuating in the arterial phase with rapid washout in the portal venous phase and iso- or hypoattenuation in the delayed phase. Although rare, the possibility that peliosis hepatis may mimic the presence of hypervascular hepatocellular carcinoma has been reported in the literature. In these patients, biopsy is often necessary to reach a definitive diagnosis.
• Hepatic abscess (liver abscess): The differential diagnosis between peliosis hepatis and hepatic abscess is extremely important to avoid the percutaneous drainage of peliotic lesions, which can be dangerous and even fatal ¹¹³⁾. With regard to imaging criteria, a hepatic abscess usually presents as a mass with a multiseptated or cluster-of-grapes appearance with nonenhancing contents.
• Focal nodular hyperplasia (benign tumor that forms in the liver): Focal nodular hyperplasias are typically homogeneously hyperattenuating masses on the arterial phase and isoattenuating on the portal venous and delayed phases. These lesions often have a central scar with low attenuation on the arterial and portal venous phases and enhancement on the delayed phase images. When such typical imaging characteristics of focal nodular hyperplasia are present, the differential diagnosis with peliosis hepatis can be achieved easily. Atypical forms of focal nodular hyperplasia may not show the characteristic enhancement patterns and the central scar just described, however, and thus pose some problems in the differential diagnosis with peliosis hepatis.
• Hepatic adenoma (an uncommon solid, benign liver lesion that develops in an otherwise normal-appearing liver) may contain fat
• Hypervascular metastases: Although some hypervascular metastases with fibrotic change can show mild hyperattenuation in the delayed phase, hypervascular metastases are usually totally hypoattenuating or isoattenuating in the delayed phase of contrast enhancement because of the rapid washout of contrast material. Thus, in general, peliotic lesions are rarely confused with hypervascular metastases.
  
• Hepatic sinusoidal dilation: usually the enhancement pattern is different on CT/MRI ¹¹⁴⁾

Peliosis hepatis treatment

Peliosis hepatis treatment depends on the cause. When a causative drug or toxin is suspected, withdrawal of that agent may result in resolution. If peliosis hepatis seen in the setting of HIV/AIDS, antibiotic treatment may be effective in eradicating B. henselae. If focal and hemorrhagic, surgical resection may also be beneficial ¹¹⁵⁾.

It is important not to drain peliosis, having mistaken it for a hepatic abscess, as bleeding can be life threatening ¹¹⁶⁾.

Peliosis hepatis prognosis

The progression of peliosis hepatis is still largely uncertain ¹¹⁷⁾. Researchers have not observed any apparent patterns of peliosis hepatis disease progression. The natural course of peliosis hepatis is regression after drug withdrawal, cessation of steroid therapy, or resolution of an associated infectious disease ¹¹⁸⁾. However, peliosis hepatis can become worse asymptomatically and present as an accidental finding that occurs during investigations of other diseases or on the autopsy table ¹¹⁹⁾, ¹²⁰⁾. A pseudotumoral and hemorrhagic evolution has also been described ¹²¹⁾, ¹²²⁾.

Some authors claim that peliosis hepatis could be associated to liver failure with clinical features of hepatomegaly, portal hypertension, cholestasis, liver rupture leading to intraperitoneal hemorrhage (internal bleeding in which blood gathers in your peritoneal cavity) or shock and, more rarely, in cirrhotic patients positive for hepatitis C virus ¹²³⁾, ¹²⁴⁾, ¹²⁵⁾ or in cases of rupture of peliosis hepatis lesions with hemoperitoneum and hemodynamic decompensation with lethargy and abdominal pain ¹²⁶⁾, ¹²⁷⁾, ¹²⁸⁾, ¹²⁹⁾. In general, if untreated, ruptured peliosis hepatis may be rapidly fatal ¹³⁰⁾.

In other cases, especially when peliosis hepatis occurs at very young age, the disease shows important effects of compression with stenosis of the vena cava ¹³¹⁾.

In still other cases, after the interruption of the steroid therapy or the resolution of the subsequent infections, a total regression was noticed ¹³²⁾, ¹³³⁾, ¹³⁴⁾. Peliosis hepatis regression can also occur without any connection with the past medical history, especially in those cases (20% to 50%) that do not allow association of peliosis hepatis to any kind of etiology ¹³⁵⁾.

Even though some authors support possible transplantation in acute liver failure cases or to use hepatectomy for the diagnosis and treatment of peliosis hepatis, surgery is more and more often used in urgent cases as treatment for the bleeding that may occur. At the same time, for the same issue, some authors proposed embolization that may be performed by an interventional radiologist or during the operation or the laparoscopic biopsy ¹³⁶⁾, ¹³⁷⁾.

Spleen peliosis

Spleen peliosis also called peliosis of the spleen, splenic peliosis or peliosis lienalis is an extremely rare benign blood vessel condition characterized by multiple, randomly distributed, blood-filled and cyst-like cavities throughout the spleen ¹³⁸⁾, ¹³⁹⁾. The size of the lesions may vary from 1 millimetrer to several centimeters ¹⁴⁰⁾. Peliosis is a term derived from the Greek pelios, which means “dusky” or “purple,” referring to the color of the liver tissue with peliosis ¹⁴¹⁾, ¹⁴²⁾. Spleen peliosis has also been reported, either alone ¹⁴³⁾, ¹⁴⁴⁾, ¹⁴⁵⁾, ¹⁴⁶⁾ or with peliosis hepatis (hepatic peliosis or liver peliosis) ¹⁴⁷⁾, ¹⁴⁸⁾, ¹⁴⁹⁾, ¹⁵⁰⁾, ¹⁵¹⁾, ¹⁵²⁾, ¹⁵³⁾. Spleen peliosis often presents with spontaneous rupture of the spleen and requires urgent surgical intervention ¹⁵⁴⁾), ¹⁵⁵⁾, ¹⁵⁶⁾, ¹⁵⁷⁾, ¹⁵⁸⁾, ¹⁵⁹⁾, ¹⁶⁰⁾, ¹⁶¹⁾, ¹⁶²⁾, ¹⁶³⁾, ¹⁶⁴⁾, ¹⁶⁵⁾, ¹⁶⁶⁾, ¹⁶⁷⁾, ¹⁶⁸⁾. Numerous associations with medications and other conditions have been described in the literature, emphasizing the limited understanding of spleen peliosis ¹⁶⁹⁾. However, spleen peliosis may also be recognized as an incidental finding on computed tomography (CT) scans or at autopsy ¹⁷⁰⁾, ¹⁷¹⁾, ¹⁷²⁾, ¹⁷³⁾, ¹⁷⁴⁾, ¹⁷⁵⁾, ¹⁷⁶⁾, ¹⁷⁷⁾.

Spleen peliosis may be idiopathic or associated with infections such as tuberculosis and Bartonella, hematological diseases such as myeloma, myelofibrosis, and Hodgkin’s disease and with the use of androgenic steroids and erythropoetin. Patients with isolated splenic peliosis may be asymptomatic or describe abdominal discomfort. It is often detected as an incidental finding on abdominal imaging or when spontaneous rupture occurs.

Spleen peliosis discovered on imaging should immediately prompt further evaluation. A differential diagnosis will often include malignant, infiltrative, or infectious conditions, as well as post-traumatic splenic cysts. The cysts of spleen peliosis are blood-filled and innumerable in quantity, distinguishing them from post-traumatic fluid-filled cysts of the spleen. Isolated peliosis of the spleen is extremely rare, and is therefore infrequently considered ¹⁷⁸⁾, ¹⁷⁹⁾, ¹⁸⁰⁾, ¹⁸¹⁾. Imaging modalities for further assessing the spleen vary given the reason for testing and the differential diagnosis; they often include ultrasound, CT, positron emission tomography with CT (PET-CT), and magnetic resonance imaging ¹⁸²⁾, ¹⁸³⁾, ¹⁸⁴⁾. Despite these various imaging modalities, imaging may be inadequate for establishing a clear diagnosis ¹⁸⁵⁾, ¹⁸⁶⁾. While spleen peliosis often exists without symptoms, atraumatic spleen rupture, requiring urgent surgical intervention is a well-established presentation of spleen peliosis ¹⁸⁷⁾), ¹⁸⁸⁾, ¹⁸⁹⁾, ¹⁹⁰⁾, ¹⁹¹⁾, ¹⁹²⁾, ¹⁹³⁾, ¹⁹⁴⁾, ¹⁹⁵⁾, ¹⁹⁶⁾, ¹⁹⁷⁾, ¹⁹⁸⁾.

As there are no clear published guidelines on the management of spleen peliosis, the definitive management of splenic rupture due to peliosis is emergency splenectomy ¹⁹⁹⁾, ²⁰⁰⁾, ²⁰¹⁾, ²⁰²⁾. However, prophylactic splenectomy is still debatable if accidental radiological findings were established upon regular check-ups or unrelated complaints ²⁰³⁾.

Figure 4. Spleen peliosis

Footnotes: Contrast-enhanced CT scan from a 44-year-old otherwise healthy man presented with left-upper quadrant and left-shoulder pain. The patient denied trauma. A CT scan revealed splenomegaly with multiple splenic cysts and free intraperitoneal fluid consistent with blood. (A) Coronal view, (B) Axial view at the level of L1, (C) Axial view at the level of T12. Significant splenomegaly (14 × 11 × 9 cm). Multiple, loculated, cystic lesions are noted throughout the spleen. The largest cystic lesion measures 9.3 cm in diameter. A minor hemoperitoneum (not visible) was present on the scan.

[Source ²⁰⁴⁾ ]

Figure 5. Spleen peliosis ultrasound

Footnote: A 3-year-old girl with splenic peliosis. Longitudinal ultrasonography of the spleen shows splenomegaly and multiple poorly defined hypoechoic nodules (arrow).

[Source ²⁰⁵⁾ ]

Figure 6. Spleen peliosis rupture

Footnotes: (A) Spleen ultrasound appearance at diagnosis. (B) Ultrasound spleen appearance in peliosis rupture. Ultrasonographic imaging showed inhomogeneous splenic parenchyma and increased size. (C) Abdominal computer tomography (CT) frame. CT showed hemoperitoneum and marked splenomegaly (with a pole-to-pole diameter of about 200 mm) with many hyperdense areas.

[Source ²⁰⁶⁾ ]

Spleen peliosis cause

The cause of spleen peliosis remains unclear ²⁰⁷⁾. Several causative factors were suggested to be associated with peliosis in the spleen, including the following: intravenous drug abuse, the usage of anabolic steroids, danazol, chronic alcohol use, granulocyte colony-stimulating factor (GSCF) use, tamoxifen, azathioprine, androgens, chemotherapy, liver cirrhosis, tuberculosis, oral contraceptive pills, human immunodeficiency virus (HIV), Hodgkin’s disease, aplastic anemia, and myeloma ²⁰⁸⁾, ²⁰⁹⁾, ²¹⁰⁾, ²¹¹⁾, ²¹²⁾, ²¹³⁾, ²¹⁴⁾, ²¹⁵⁾, ²¹⁶⁾, ²¹⁷⁾, ²¹⁸⁾, ²¹⁹⁾, ²²⁰⁾, ²²¹⁾, ²²²⁾, ²²³⁾, ²²⁴⁾, ²²⁵⁾, ²²⁶⁾, ²²⁷⁾, ²²⁸⁾, ²²⁹⁾, ²³⁰⁾, ²³¹⁾. A number of reported patients were also noted to have blood disorders including multiple myeloma, aplastic anemia, Hodgkin disease, and myelofibrosis ²³²⁾, ²³³⁾, ²³⁴⁾, ²³⁵⁾, ²³⁶⁾, ²³⁷⁾, ²³⁸⁾, ²³⁹⁾, ²⁴⁰⁾, ²⁴¹⁾.

Preliminary evidence links the development of peliosis to angiogenesis (formation of new blood vessels) due to elevated levels of vascular endothelial growth factor (VEGF) ²⁴²⁾. VEGF is a fundamental regulator of physiologic angiogenesis. Elevated VEGF levels are known to be associated with tumor progression and poor outcomes in a number of cancers. A condition resembling peliosis has been demonstrated in mice with elevated VEGF levels, that were found to have massively dilated hepatic sinusoids and endothelial cell proliferation and apoptosis ²⁴³⁾. The experimental link to elevated VEGF levels, warrants investigation into the treatment of peliosis with anti-angiogenic factors ²⁴⁴⁾.

Spleen peliosis risk factors include:

• use of anabolic steroids
• hematological conditions such as aplastic anemia
• wasting diseases such as
• tuberculosis
• AIDS
• concurrent malignancy

Spleen peliosis symptoms

Patients with spleen peliosis are commonly asymptomatic, and splenic peliosis may present as an incidental finding during imaging studies for other diseases, at autopsy, or with spontaneous rupture of the spleen after minimal or no trauma ²⁴⁵⁾. Although uncommon, some reports suggest that males, ages > 20 years, presence of splenomegaly, and use of chemotherapy might be associated with increased risk of spontaneous splenic rupture in hematology ²⁴⁶⁾. One literature review has shown that all the reported spleen peliosis cases collected from 1980 till 2016 had either presented with abdominal pain or circulatory shock ²⁴⁷⁾. Most cases of spleen peliosis are associated with peliosis hepatis (peliosis of the liver) ²⁴⁸⁾.

Spleen peliosis diagnosis

Spleen peliosis hepatis is very difficult to diagnose because it is usually asymptomatic, and extreme rarity. Peliosis diagnosis is usually obtained after histopathological examination of the resected organ or at autopsy. Radiological imaging shows a broad spectrum of appearances because of its dependence on the blood supply to the lesions. Ultrasound shows multiple poorly defined hypoechoic lesions (Figure 4) and hyperechoic thrombosis ²⁴⁹⁾. The finding of cyst-like hypodense lesions which do not cause mass effect on vessels on contrast-enhanced CT should alert the radiologist to the diagnosis of spleen peliosis. This is of importance in recognizing the risk of spontaneous splenic rupture and in avoiding interventional procedures, such as liver biopsy or percutaneous transhepatic cholangiography, which may precipitate life-threatening iatrogenic organ rupture.

Peliosis histological appearance is characterized by multiple blood-filled cystic cavities primarily involving the mononuclear phagocytic system (liver, spleen, bone marrow, and lymph nodes).

Once the presence of peliosis has been established it is proposed that all necessary investigations be pursued to detect its presence in other organs and to establish a possible cause ²⁵⁰⁾. The implications for this are clear. Spontaneous rupture of the spleen remains an ever-present threat. Physicians should be mindful of this in the event that anticoagulation or thrombolysis is being considered. In addition, the presence of peliosis may prompt the investigation and subsequent discovery of equally serious underlying conditions, for example immunodeficiency or malignancy.

Spleen peliosis treatment

Hemorrhage associated with splenic peliosis is quite amenable to surgical therapy if recognised and treated promptly ²⁵¹⁾. The existing literature does not however explore the surgical management of patients in whom an incidental diagnosis of splenic peliosis has been made. The introduction of laparoscopic splenectomy has reduced significant morbidity when compared with open surgery ²⁵²⁾. Prophylactic laparoscopic splenectomy has been advocated to prevent organ rupture in conditions such as splenic sarcoidosis ²⁵³⁾. The role of elective splenectomy in splenic peliosis is not known.

From the patient’s perspective, lifestyle changes may be necessary. Younger patients should be encouraged to avoid high-risk activities, for example, contact sports ²⁵⁴⁾. It would seem wise to avoid or discontinue the oral contraceptive pill, and seek alternative forms of contraception. In addition any attending physician should be aware when other medications thought to cause peliosis are being considered ²⁵⁵⁾.

Bacillary peliosis

Bacillary peliosis also called bacillary peliosis hepatis or Bartonella peliosis hepatis is a blood vessel condition characterized by multiple, randomly distributed, blood-filled and cyst-like cavities throughout the liver that is secondary to Gram-negative Bartonella henselae bacteria infection in immunocompromised patients, first described in human immunodeficiency virus (HIV) infected or AIDS individuals ²⁵⁶⁾, ²⁵⁷⁾, ²⁵⁸⁾, ²⁵⁹⁾. Most patients with bacillary peliosis develop symptoms such as anorexia, weight loss, enlarged tender lymph nodes (lymphadenopathy), chills, fever, headache and malaise in addition to gastrointestinal symptoms or abdominal pain ²⁶⁰⁾, ²⁶¹⁾, ²⁶²⁾, ²⁶³⁾, ²⁶⁴⁾, ²⁶⁵⁾. Approximately 1% to 2% of patients with Bartonella infection develop severe systemic disease with involvement of the liver, spleen, bone, central nervous system (brain and spinal cord) or lung ²⁶⁶⁾. Approximately 25% of patients have lymphadenopathy (enlarged lymph nodes), but often the classic skin papule of cat-scratch disease is absent  ²⁶⁷⁾, ²⁶⁸⁾, ²⁶⁹⁾.

Bacillary peliosis hepatis patients have enlarged liver (hepatomegaly), and some also have enlarged spleen (splenomegaly). One-quarter of the patients also had skin bacillary angiomatosis (cutaneous bacillary angiomatosis) lesions. Abdominal CT of the peliotic liver usually reveals numerous hypodense lesions, but this appearance is not specific for bacillary peliosis; therfore the diagnosis of Bartonella infection must be confirmed by histopathological evaluation. Additionally, some HIV-infected patients with hepatic Bartonella infection develop inflammatory nodules in the liver without the vascular proliferative characteristics of peliosis hepatis. Patients with splenic bacillary peliosis can have thrombocytopenia or pancytopenia and abdominal ascites.

HIV-associated bacillary peliosis hepatis is an unusual, treatable opportunistic infection that responds to antibiotics. Inadequately treated, HIV-associated bacillary peliosis can be progressive and may be fatal ²⁷⁰⁾, ²⁷¹⁾.

Figure 7. Bacillary peliosis

Footnotes: Bacillary peliosis in a 32-year-old man with HIV/AIDS who presented with fever. (a) Axial in-phase T1-weighted MR image shows an ill-defined iso-to mildly hypointense nodule in the posterior segment of the right hepatic lobe (arrow). (b) Axial fat-saturated T2-weighted MR image shows moderate to high signal intensity of the nodule (arrow). Smaller similar subcapsular nodules are seen posteriorly (arrowheads). (c) Axial contrast-enhanced early phase fatsuppressed T1-weighted MR image shows the hypointense right hepatic nodule with irregular continuous peripheral enhancement (arrow). (d) Axial contrast-enhanced delayed phase T1-weighted MR image shows delayed enhancement within the nodule (arrowhead), which reaches a signal intensity similar to that of the surrounding hepatic venous structures because of contrast agent retention within dilated sinusoids in the lesion.

[Source ²⁷²⁾ ]

Figure 8. Bartonella bacteria

Footnote: Warthin-Starry stain demonstrating the characteristic pleomorphic bacilli of Bartonella bacteria in bone marrow core biopsy

[Source ²⁷³⁾ ]

Bacillary peliosis cause

Bartonella henselae the bacteria that cause bacillary peliosis commonly cause cat scratch disease or cat scratch fever ²⁷⁴⁾, ²⁷⁵⁾, ²⁷⁶⁾, ²⁷⁷⁾, ²⁷⁸⁾, ²⁷⁹⁾,²⁸⁰⁾, ²⁸¹⁾. People become infected with Bartonella henselae from the scratch of domestic or feral cats, particularly kittens ²⁸²⁾, ²⁸³⁾, ²⁸⁴⁾, ²⁸⁵⁾. Cats can have fleas that carry Bartonella henselae bacteria. These bacteria can be transmitted from a cat to a person during a scratch that is contaminated with flea stool. Infected cats that lick a person’s open wound or bite can also spread Bartonella henselae bacteria. Some evidence suggests that these bacteria may spread directly to people by the bite of infected cat fleas, but this has not been proven.

Bartonella henselae infection or cat scratch disease occurs most often in children under the age of 15 (children 5 to 10 years of age) ²⁸⁶⁾, ²⁸⁷⁾, ²⁸⁸⁾. Though more common in the southeast, cat scratch disease occurs throughout the United States. Stray cats are more likely than pets to be infected with B. henselae. In the United States, most cases of cat scratch disease occur in the fall and winter.

Bacillary peliosis symptoms

Most patients with bacillary peliosis develop symptoms such as anorexia, weight loss, enlarged tender lymph nodes, chills, headache, malaise and fever in addition to gastrointestinal symptoms or abdominal pain ²⁸⁹⁾, ²⁹⁰⁾, ²⁹¹⁾, ²⁹²⁾, ²⁹³⁾, ²⁹⁴⁾, ²⁹⁵⁾. Approximately 1% to 2% of patients with Bartonella infection develop severe systemic disease with involvement of the liver, spleen, bone, central nervous system (brain and spinal cord) or lung ²⁹⁶⁾. Approximately 25% of patients have lymphadenopathy (enlarged lymph nodes), but often the classic skin papule of cat-scratch disease is absent  ²⁹⁷⁾, ²⁹⁸⁾, ²⁹⁹⁾.

. Bacillary peliosis can cause splenic peliosis and peliosis hepatis. Rupture with intraabdominal hemorrhage has previously been reported in both peliosis hepatis ³⁰⁰⁾ and peliosis of the spleen ³⁰¹⁾, ³⁰²⁾ and is another possible mode of presentation, underscoring the need for rapid diagnosis and therapy in these cases.

Bacillary peliosis diagnosis

Bacillary peliosis is very difficult to diagnose. Laboratory findings typically included a mild-to-moderate elevation of the serum aminotransferase level (alanine aminotransferase (ALT) and  aspartate aminotransferase (AST)) and a moderate-to-severe elevation of the alkaline phosphatase (ALP) level in association with a normal or only mildly elevated bilirubin level ³⁰³⁾. Progressive reduction in the number of blood cells (pancytopenia) occurred in some patients. Imaging studies showed enlarged abdominal lymph glands and a heterogeneous hepatic or splenic parenchyma in some cases ³⁰⁴⁾.

Liver lesions are typically multiple and associated with abdominal lymphadenopathy and, in some cases, splenic lesions; many patients come to biopsy to exclude tumors ³⁰⁵⁾, ³⁰⁶⁾, ³⁰⁷⁾. On laparotomy, the liver may be found to be studded with hard nodules of varying sizes ³⁰⁸⁾.

Biopsy findings

Liver biopsy showed the presence of multiple blood-filled cystic spaces, foci of necrosis, fibromyxoid stroma, and clumps of granular purple material that correspond to organisms on Warthin-Starry stain and electron microscopy ³⁰⁹⁾.

Bartonella infection may cause vascular proliferative lesions in the liver. Bacillary epithelioid angiomatosis is a vasoproliferative tissue reaction to Bartonella henselae or Bartonella quintana that usually occurs in immunocompromised hosts. Hepatic involvement shows sharply demarcated periportal areas in which the normal parenchyma is replaced by vascular tissue with extravasated erythrocytes, delicate spindle cells, neutrophils, and karyorrhexic debris, mimicking Kaposi sarcoma ³¹⁰⁾. Similar lesions have been designated as bacillary peliosis hepatis; these are characterized by the presence of multiple blood-filled cystic spaces, foci of necrosis, fibromyxoid stroma, and clumps of granular purple material that correspond to organisms on Warthin-Starry stain and electron microscopy ³¹¹⁾. Bacillary peliosis hepatis can be mistaken for nonbacillary peliosis hepatis.

The hallmark lesion in hepatic cat-scratch disease is an irregular, stellate microabscess surrounded by a layer of palisading histiocytes, lymphocytes, and a rim of fibrous tissue ³¹²⁾, ³¹³⁾, ³¹⁴⁾. Younger lesions may show more necrosis with less organization of the inflammatory granulomatous response, whereas older lesions may show confluent granulomas with scarring and scant residual necrosis ³¹⁵⁾. These hepatic lesions are similar to the ones seen in lymph nodes in patients with cat-scratch disease, but they have also been noted in infections with Y. enterocolitica, F. tularensis, lymphogranuloma venereum, mycobacterial species, Candida, and Actinomyces ³¹⁶⁾. Other lesions may appear as small, rounded granulomas with giant cells and small foci of central necrosis, similar to caseating granulomas in mycobacterial or fungal infections. The background liver parenchyma shows sinusoidal dilatation, portal mixed but predominantly lymphocytic inflammatory infiltrates, portal fibrosis, periductal concentric fibrosis, and focal bile ductular proliferation ³¹⁷⁾. These changes are attributed to mass effect and are also seen in other infections that result in space-occupying lesions, such as pyogenic abscesses ³¹⁸⁾.

Warthin-Starry stains identify Bartonella bacteria in some cases (see Figure 5) and the organisms often cluster around vessels or along collagen fibers; the stain is not specific for the organism ³¹⁹⁾. Culture is difficult. The diagnosis can be confirmed by polymerase chain reaction (PCR) and Southern blot for Bartonella DNA on tissue, skin testing, or serology ³²⁰⁾, ³²¹⁾, ³²²⁾, ³²³⁾.

Bacillary peliosis treatment

Bacillary peliosis is treated with antibiotic. Azithromyin, doxycycline, and gentamicin are all considered effective against Bartonella but the regimen of azithromycin and/or doxycycline is most commonly used in solid organ recipients ³²⁴⁾. Macrolides (e.g., clarithromycin, azithromycin, erythromycin, clarithromycin, roxithromycin) also have immunomodulatory effects, which include reducing vascular endothelial growth factor (VEGF) activity, which may have additional benefits for Bartonella vascular lesions ³²⁵⁾. The duration of therapy is not well-defined though given the high risk for morbidity in the immunosuppressed population and the propensity for relapse of Bartonella infections, a prolonged duration of antimicrobial therapy is typically favored ³²⁶⁾.

Antibiotic treatment of bacillary angiomatosis and bacillary peliosis hepatis has never been studied systematically. Two criteria must be met to achieve successful eradication of Bartonella infections in the immunocompromised patient: first, the specific strain of Bartonella henselae and Bartonella quintana infecting the patient must have excellent in vivo susceptibility to the prescribed antibiotic, and second, the treatment must be of sufficient duration to prevent relapse ³²⁷⁾. The first patient with bacillary angiomatosis to be described was treated empirically with erythromycin, and the lesions resolved completely³²⁸⁾. Subsequently, erythromycin has become the drug of first choice and has successfully been used to treat many patients with bacillary angiomatosis ³²⁹⁾, ³³⁰⁾. Treatment of bacillary angiomatosis and bacillary peliosis hepatis with oral doxycycline (100 mg twice daily) has also been consistently successful ³³¹⁾. Lesions resolved in several patients treated with ceftriaxone or fluoroquinolone compounds ³³²⁾, ³³³⁾, but the progression of bacillary angiomatosis lesions in patients has been observed during treatment with ciprofloxacin ³³⁴⁾. Additionally, a Bartonella species has been isolated from the blood or bacillary angiomatosis lesions of patients being treated with narrow-spectrum cephalosporins ³³⁵⁾, nafcillin, gentamicin, and trimethoprim-sulfamethoxazole (but never from patients being treated with a macrolide, rifamycin, or a tetracycline) ³³⁶⁾. Experts therefore do not recommend fluoroquinolones, trimethoprim-sulfamethoxazole, or narrow-spectrum cephalosporins for the treatment of bacillary angiomatosis or bacillary peliosis hepatis ³³⁷⁾. Treatment failures have been reported with many different antibiotics, and these are usually attributable to a lack of susceptibility of Bartonella in vivo and/or an insufficient duration of therapy ³³⁸⁾, ³³⁹⁾.

The drug of choice for the treatment of bacillary angiomatosis is erythromycin given p.o. (500 mg p.o. four times daily) for 3 months, but intravenous (IV) administration should be used in patients with severe disease ³⁴⁰⁾. Patients intolerant of erythromycin can be treated with doxycycline (100 mg p.o. or i.v. twice daily) ³⁴¹⁾, ³⁴²⁾, ³⁴³⁾. The response to treatment appears to be equivalent whether erythromycin or doxycycline is prescribed ³⁴⁴⁾. Combination therapy, with the addition of rifampin (300 mg p.o. twice daily) to either erythromycin or doxycycline, is recommended for immunocompromised patients with acute, life-threatening Bartonella infection. The intravenous route is especially important in cases of gastrointestinal intolerance or poor absorption. The combination of doxycycline and rifampin is preferred for the treatment of patients with CNS Bartonella infection because of the superior CNS penetration of doxycycline compared with those of the other first-line antibiotics.

The response to treatment can be dramatic in immunocompromised patients. In one patient who received a single 250-mg oral dose of erythromycin, blood cultures became sterile and a palpable subcutaneous lesion disappeared within hours (but recurred months later). More chronic lesions resolve more slowly, but after approximately 4 to 7 days of therapy, cutaneous bacillary angiomatosis lesions usually improve and resolve completely after 1 month of treatment ³⁴⁵⁾. Bacillary bacillary peliosis hepatis responds more slowly than cutaneous bacillary angiomatosis, but hepatic lesions should improve after several months of treatment.

Relapses of bacillary peliosis hepatis and bacillary angiomatosis lesions in bone and skin have been reported frequently ³⁴⁶⁾, ³⁴⁷⁾, ³⁴⁸⁾, ³⁴⁹⁾. Relapses occur when antibiotics are given for a shorter duration (<3 months), especially in severely immunocompromised HIV-infected patients ³⁵⁰⁾, ³⁵¹⁾. For this reason and from extensive experience treating patients with bacillary angiomatosis and bacillary peliosis hepatis, experts recommend that treatment be given for at least 3 months for bacillary angiomatosis and 4 months for bacillary peliosis hepatis ³⁵²⁾, ³⁵³⁾. All immunocompromised patients with a Bartonella infection should receive antibiotic therapy (erythromycin 500 mg p.o. four times daily or doxycycline 100 mg p.o. twice daily); patients who have relapses after the recommended treatment should then receive secondary prophylactic antibiotic treatment with erythromycin (500 mg p.o. four times daily) or doxycycline (100 mg p.o. twice daily) as long as they are immunocompromised ³⁵⁴⁾. Of note, AIDS patients receiving prophylaxis with a macrolide or rifamycin antibiotic for Mycobacterium avium complex infection appear to be protected from developing infections with Bartonella species ³⁵⁵⁾. Some immunocompromised patients develop a potentially life-threatening Jarisch-Herxheimer-like reaction within hours after institution of antibiotic therapy ³⁵⁶⁾. Physicians should advise patients of this possible treatment complication, and patients with severe respiratory and/or cardiovascular compromise should be monitored carefully following institution of antimicrobial therapy ³⁵⁷⁾.