—  SYMPOSIUM #50  —

Opportunistic Infections in Immunocompromised Patients
Moderator: Dr. Paul Hofman

Section 1 - Bacterial Infections in the Immunocompromised Host

Martin J. Hale
Division of Anatomical Pathology, Chris Hani Baragwanath Laboratory
School of Pathology, University of the Witwatersrand and National Health Laboratory Service
Johannesburg , South Africa


Immunocompromised hosts have always been susceptible to a wide range of infections and are often difficult to treat, not only because of the impaired immunity but also because of the co-existent or underlying condition that is resulting in the immunosuppression.

With the advent of the Acquired Immunodeficiency Syndrome (AIDS) and the discovery of the Human Immunodeficiency Virus (HIV) a cohort of patients was suddenly produced that thrust immunodeficiency into the limelight and the infections that are associated with it. Suddenly the practice of medicine changed overnight; not only did these infections become more frequent but there were two added difficulties that the profession had to overcome, the first being the range of infections, including those that were considered rare and the second the realisation that traditional teaching and current knowledge in respect of the presentation, symptoms and morphology of disease was no longer valid. Furthermore some diseases had not been experienced by the practicing physician or had yet to be discovered and classified. Infections became difficult to identify and treatment was delayed, however with the passage of time diagnostic skills have improved and with it, patient care.

Bacterial infections, common and exotic or old and new, were included in this diagnostic milieu. Diseases that were being brought under control made a resurgence, the best example of this being tuberculosis, whilst other unusual mycobacterial infections were frequently identified. Consequently interest in mycobacteria surged.

They are an extremely successful genus, having a ubiquitous distribution throughout the world in soil, water, and air resulting in frequent host contact and infection throughout the animal kingdom including humans. They have a unique bacterial wall that is responsible for their long-term survival and viability in the environment and their hosts. They induce a spectrum of pathological responses unparalleled by other infections, brought about as an interplay between their multi-environmental presence and the varied immunological responses of the host.

The mechanisms enabling mycobacteria to survive intracellularly are largely unknown but recent work has suggested that modification of biochemical interactions within the phagosome is responsible. These include exclusion of proton-ATPase resulting in limited acidification [1]within the phagosome and a coat protein, TACO (tryptophane aspartate-containing coat protein). The latter is actively recruited to and retained on phagosomes by viable mycobacteria preventing their delivery to lysosomes for subsequent destruction [2].

Tuberculosis
Tuberculosis is the archetypical example of mycobacterial infection in humans. It is caused by Mycobacterium tuberculosis and has over the centuries, been responsible for disease and death in all social strata. It is historically significant, being regarded as a scourge of society and often destroying whole families: "Consumption has taken the whole five... Why life is so blank, brief and bitter I do not know," wrote Charlotte Bronte, describing the loss of her mother, four sisters and one brother to tuberculosis. She was later to die of the same disease.

During the twentieth century considerable advances were made against tuberculosis but with the advent of the global HIV pandemic, the number of new cases of tuberculosis has risen alarmingly and in third world countries has assumed epidemic proportions [3]. This has resulted in an increased need for control and improved diagnosis, with histopathologists playing a vital role in the recognition of the many guises that the disease can present.

The classic histopathological picture of tuberculosis is the caseating granuloma but this may show considerable variation. Classically, the granuloma comprises epithelioid cells with abundant eosinophilic cytoplasm. A central focus of caseous necrosis is present and there is a cuff of mature lymphocytes. The epithelioid cells are so named because of the morphological change that the macrophages undergo after activation, acquiring large amounts of eosinophilic cytoplasm thereby resembling epithelial cells. In practice this is seldom seen. Instead the epithelioid cell often appears as a spindle cell with a plumper nucleus than a fibroblast. The nucleus also has a slightly twisted, buckled appearance as though it has been rotated longitudinally about its centre through 45 degrees. Cytoplasmic borders are indistinct. The caseous necrosis may vary, from complete absence to cases where a surgical specimen, such as a lymph node, is almost entirely replaced by this material, requiring a careful search to establish the presence of epithelioid histiocytes and a histopathological diagnosis of tuberculosis.

In some instances an infiltrate of acute inflammatory cells may be identified within the caseous area. Coupled with a granulomatous inflammatory response, it raises the possibility of a deep fungal infection.

The presence of caseous necrosis, whilst highly suggestive of tuberculosis, is not specific as it may be found in association with cryptococcosis and histoplasmosis. The necrosis found in the centre of the granuloma in cases of necrotising sarcoidosis may resemble caseation, and distinction between these may be particularly difficult, if not impossible, on morphological grounds alone. A toxic glycolipid component of the mycobacterial cell wall may be responsible for induction of caseation [4].

M tuberculosis bacilli are best identified in tissue sections using the Ziehl-Neelsen or Triff stains. The latter stain is particularly good at demonstrating the organisms and the background tissue allowing the histopathologist to better visualise and correlate the pathological process, especially important if scanty bacilli are present. The slender, rod shaped and slightly curved organisms are acid-fast, stain intensely red with carbolfuchsin and are found in the granuloma either within the caseous centre or amongst the epithelioid histiocytes. The detection of acid-fast bacilli in granulomas may be problematic and is largely dependent on the underlying response that is initiated by the patient's immune system. In those patients in whom there is a vigorous granulomatous reaction, few, if any, bacilli are found and confirmation of the disease depends on culture or molecular identification of mycobacterial genomic material [5]. Silver impregnation methods such as the Dieterle or Warthin Starry are more sensitive and may be used to assist with the identification of mycobacteria in those cases where carbolfuchsin methods have failed [6]; they show beaded bacilli, nocardia-like filamentous organisms, and granular debris probably representing degenerate mycobacteria. Their specificity is limited as morphologic similarities are shared with cat scratch disease and nocardiosis. In addition, the visual interpretation of the stain and correlation with the underlying pathological changes is lost. Fluorescence microscopy using the auramine-rhodamine and Papanicolaou stains may also be used to identify bacilli in cytological specimens [7]. An immunohistochemical detection method has also been developed [8].

Pathology of Mycobacterium Avium-Intracellulare
Many diseases are caused by mycobacteria other than tuberculosis (MOTT), with those belonging to the Mycobacterium avium complex (MAC) being the commonest. They include Mycobacterium avium and Mycobacterium intracellulare. M avium was identified in 1890 in chickens and M intracellulare in 1969 [9].

Histopathological changes in MAC infection are extremely variable and linked to the immune status of the patient. Granuloma formation accompanied by necrosis is seen in those who are immunocompetent whilst those who are immunodeficient, such as AIDS patients, may show subtle pathological changes. A high index of suspicion is required when examining tissue from the latter group of patients. The infection may manifest as easily discernible aggregates of foamy histiocytes in the major organs, particularly the reticulo-endothelial system including liver, spleen and bone marrow. The paracortical regions of lymph nodes and the lamina propria of the intestinal mucosa may show extensive infiltration by infected histiocytes. In many instances the infiltration is more subtle and comprises singly lying histiocytes, which may be undetected on H&E examination. The use of the Ziehl-Neelsen stain will reveal infected histiocytes containing numerous intracellular arrays of acid-fast bacilli supporting the routine use of this stain on all biopsies from immunodeficient patients.

Pathology of Mycobacterium Kansasii Infection.
After MAC infection, Mycobacterium kansasii is the second most common non-tuberculous infection in patients with AIDS [10], but has also been identified in HIV negative patients. South African gold miners with a background of silicosis or old tuberculous scarring have increased susceptibility to this infection, which is most often found in the lungs [11].

Mycobacterial Pseudotumour.
Mycobacterial infection may present as a spindle cell pseudotumour which has been described in several sites including lymph nodes, bone marrow, skin, lung and spleen [12, 13, 14] and secondary to various Mycobacteria including M avium-intracellulare, M kansasii, M gordonae and M tuberculosis. Recognition is important as the infection is easily confused with a neoplastic lesion. Histological examination shows characteristic spindle cell proliferation in a storiform pattern, and in a lymph node, may obliterate the nodal architecture. Vascularity may be prominent and there is increased reticulin fibre deposition. Mitotic activity, sometimes frequent, may be found. Occasional cells with foamy cytoplasm and multinucleate histiocytes may be present along with scattered lymphocytes and plasma cells in the background, providing clues to the diagnosis. Ziehl-Neelsen staining shows large numbers of intracytoplasmic acid-fast bacilli. The architecture closely resembles that of a mesenchymal neoplasm, specifically that of a fibrous histiocytoma. To add to the confusion, the cytoplasm of the spindle cells may be positive immunohistochemically with a number of cytoskeletal antibodies, desmin being the commonest, leading to an erroneous diagnosis of a smooth muscle tumour [15]. Immunoreactivity to vimentin and S-100 protein may be present and a positive reaction to lysozyme and alpha 1 antichymotrypsin confirms the histiocytic origin of the proliferating cells [12, 16]. Electron microscopy fails to demonstrate intracytoskeletal fibres and other features expected of myoid differentiation but shows intracytoplasmic lysosomes and large numbers of bacilli [15]. Coexistent mycobacterial pseudotumour and Kaposi's sarcoma in lymph nodes has been described [16] and as these are common manifestations of the AIDS, awareness is important as the presence of Kaposi's sarcoma alters treatment and prognosis. Immunohistochemistry is able to distinguish between the two pathological processes, S-100 protein being a sensitive marker for the spindle cell component of the mycobacterial pseudotumour and CD 31, CD 34 and Human Herpesvirus 8 being positive in the spindle cells of Kaposi's sarcoma. The explanation for S-100 positivity of the histiocytes is unexplained.

Cytological Diagnosis of Mycobacterial Disease.
Fine needle aspiration of lymph nodes in patients with lymphadenopathy is a useful diagnostic modality for tuberculosis in developing countries and has been used with varying success in the diagnosis of mycobacterial lymphadenitis in developed countries. In the United States fine needle aspiration identified 46% of 238 patients with mycobacterial infection [17] but was not found to be a reliable diagnostic test in New Zealand [18].

Leprosy
Given our current understanding of the immune system and its application in the explanation of the polar forms of leprosy it could be expected that there would be a dramatic increase in cases of leprosy as a consequence of the AIDS epidemic. This has proved not to be the case in the majority of studies [19, 20, 21], the exception being a study from Tanzania that showed HIV seroprevalence to be positively associated with leprosy [22]. There has been no noticeable shift in the number of multibacillary cases compared with paucibacillary leprosy, but there is evidence that the incidence of reactional leprosy is increased in HIV positive patients [23].

Spirochaetosis
Intestinal spirochaetosis is an infection that is typically associated with HIV infected individuals and homosexuals. The main infecting organisms in human patients are Brachyspira aalborgi and Brachyspira pilosicoli with infection rates appearing to be higher in patients from lower socio economic groups [24]. The disease has a worldwide distribution and may be found in patients presenting with a wide range of intestinal symptoms, many of which are non-specific. Often the infection appears in association with faecal stasis and is found in patients with colorectal carcinoma, megacolon, diverticulitis and appendicitis. Other associations include colonisation of adenomatous polyps [25], and infection in children [26]. In the immunocompromised setting, patients often present with diarrhoea that is sometimes accompanied by haemorrhage.

The organism colonises the large bowel and is identified pathologically as a prominent basophilic layer of about 3 microns on the luminal surface of the enterocytes. As this feature mimics the epithelial brush border it can be easily overlooked and the diagnosis missed by the unwary pathologist. The organism may be stained by a variety of special stains including the Warthin-Starry, periodic acid-Schiff and Giemsa stains. The infection is usually limited to the luminal surface of the bowel and superficial crypts and is not accompanied by inflammatory changes in the lamina propria. Ultrastructural evidence of invasion of epithelial cells, macrophages and Schwann cells has been described [27].

Bacillary Angiomatosis
Bacillary angiomatosis was initially identified in HIV positive patients as a cutaneous vasoformative lesion, which resembled a pyogenic granuloma both clinically and pathologically. Initially a causal relationship was suggested with cat scratch disease and its infectious agent Afipia felis but with time it was recognised that different agents, Bartonella henselae and B quintana were responsible. B henselae is regarded as a zoonosis with reservoirs in domestic cats and fleas and that these are the source of infection for immunocompromised patients.

Typically the patient presents with a cutaneous lesion that resembles a pyogenic granuloma. Superficial ulceration may be present. Histological examination shows proliferation of thin walled capillaries in a collagenous stroma that shows focal aggregation of inflammatory cells, usually neutrophils. Importantly, the lesion lacks the lobular organisation of a pyogenic granuloma. In addition careful search shows extracellular clumps of finely granular, eosinophilic, basophilic or even amphophilic material lying within the stroma, these being the infecting bacilli. Often this material is erroneously identified as fibrinous deposits, especially given the context of a proliferative, vasoformative nodule in which it is found. Morphologically, the bacilli are small, measuring about 3 microns in length. In addition to the H&E stain the bacteria are well demonstrated by the Warthin-Starry and Giemsa stains.

Systemic involvement may also occur with involvement of the liver and spleen causing peliosis hepatis and peliosis splenis respectively. In addition, the liver and spleen may show necrotising granulomatous inflammation. Splenic rupture has occurred in one case [28, 29]. Involvement of the eye [30], brain [31], and lymph nodes [32] has been described.

Granuloma Inguinale
Granuloma inguinale (Donovanosis) is caused by the coccobacillus, Calymmatobacterium granulomatis. It is principally a sexually transmitted disease involving the genital tract, perineal skin and subcutaneous tissue, although extra-genital infections are well described. The disease has a geographic distribution and is primarily found in tropical and sub-tropical countries.The genital ulceration caused by granuloma inguinale has been identified as a risk factor for acquiring Human Immunodeficiency virus infection [33].

A number of extra-genital sites of infection have also been described, most commonly involving the face, especially the lip and nasal region. [34, 35] Other unusual sites of reported extra-genital granuloma inguinale include the spinal cord and thoracic vertebral osteomyelitis, [36] cervical lymph nodes [37] and even soft tissue. [38] Cases of extra-genital granuloma inguinale have even been rarely described in children resulting in otitis media and mastoiditis [39] and as a neck mass in an infant [40].

Granuloma inguinale typically shows pseudoepitheliomatous hyperplasia of the epidermis adjacent to the area of ulceration accompanied by a dermal inflammatory infiltrate comprising neutrophils and plasma cells with interspersed large mononuclear histiocytic cells, the latter showing intra-cytoplasmic vacuoles containing the characteristic coccobacilliof C. granulomatis. In the HIV positive setting though, this is altered to sheets of histiocytes containing numerous intracytoplasmic coccobacilli with scanty interspersed inflammatory cells [41].

The identification of intra-cytoplasmic organisms within macrophages is often problematic and a number of entities including leishmaniasis, histoplasmosis, rhinoscleroma and malakoplakia need to be considered in the differential diagnosis.

The morphological similarity of C. granulomatis to the Klebsiella genus has been recognised for some time and recently DNA analysis has demonstrated up to 99% homology with Klebsiella [42, 43] with the suggestion that the organism be renamed Klebsiella granulomatis comb. nov.

Streptococcal Pneumonia
Infections caused by Streptococcus pneumoniae are common in immunocompromised patients and particularly in those that are HIV positive, a group that has been estimated to have a 25 to 100 fold increased risk of developing infection [44, 45, 46], particularly with progression to AIDS. The spectrum of disease includes pneumonia, meningitis and septicaemia with the pathological features being similar to those in immunocompetent patients.

Nocardiosis
Nocardiosis, caused by a Gram-positive branching bacterium, is an infection that is increasing in frequency in HIV positive patients and is often confused clinically and radiologically with tuberculosis. Commonest sites of infection include the lung, sinuses, brain, soft tissue and abdomen and there is usually a high fatality rate [47, 48, 49].

Salmonellosis
Salmonella infections are commoner in HIV positive patients when compared to the general population [50]. These are usually non-typhi infections that can be severe and recurrent with a high mortality. Suppurative sites of infection are seldom found making the diagnosis reliant on clinical suspicion and blood culture [51].

Folliculitis, other than eosinophilic folliculitis, is most often caused by Staphylococcus aureus, although in some instances infection may result from non-tuberculous mycobacteria [52].

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