Download Lymphadenopathies in HIV

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FACULTEIT GENEESKUNDE EN
GEZONDHEIDSWETENSCHAPPEN
Academiejaar 2009 - 2010
Lymphadenopathies in HIV
Alexei B. Byzov
Promotor: Prof. Dr. J. Philippé
Co-promotor: Prof. Dr. A. Pivnik
Scriptie voorgedragen in de 2de Master in het kader van de opleiding tot
MASTER IN DE GENEESKUNDE
1.
Abstract ........................................................................................................................................... 2
2.
Introduction ..................................................................................................................................... 3
3.
Materials and methods..................................................................................................................... 4
4.
Results ............................................................................................................................................. 5
4.1.
HIV virus ............................................................................................................................... 5
4.1.1.
History and epidemiology ................................................................................................. 5
4.1.2.
Biology of the virus ........................................................................................................... 5
4.1.3.
Treatment of HIV .............................................................................................................. 7
4.2.
Lymphatic system and lymph nodes: structure and function................................................. 7
4.3.
Phases of HIV infection and changes in the lymph node morphology .................................. 8
4.4.
Lymphadenopathy the main symptom of HIV infection ..................................................... 10
4.5.
Physical examination of the patient with lymphadenopathy: how to examine and what to
look for? ............................................................................................................................................ 12
4.6.
Lymphadenopathy in HIV-positive patients as a result of opportunistic infections ............ 16
4.6.1.
HIV-LA in tuberculosis ................................................................................................... 17
4.6.2.
HIV-LA in nontuberculous mycobacteriosis................................................................... 19
4.6.3.
HIV-LA in cytomegalovirus............................................................................................ 21
4.6.4.
HIV-LA in/and Pneumocystis jirovecii ........................................................................... 22
4.6.5.
Other opportunistic infections associated with HIV........................................................ 22
4.7.
Lymphadenopathy in HIV-positive patients as a result of malignancies............................. 24
4.7.1.
HIV-LA in Kaposi sarcoma............................................................................................. 25
4.7.2.
HIV-LA in Hodgkin lymphoma ...................................................................................... 27
4.7.3.
HIV-LA in Burkitt lymphoma ......................................................................................... 30
4.8.
Russian experience of 2002-2005 ........................................................................................ 35
5.
Discussion ..................................................................................................................................... 36
6.
References ..................................................................................................................................... 43
1
1. Abstract
HIV virus heeft een belangrijke invloed op wereld en het aantal geïnfecteerde mensen stijgt
progressief. Deze literatuurstudie gaat de lymfadenopathie (LA), één van de belangrijkste symptomen
van een HIV infectie, bestuderen. Verschillende infecties die LA veroorzaken bij HIV positieve
individuen worden besproken. Ook maligne aandoeningen als oorzaak voor LA bij HIV zijn
onderzocht. Klinische aspecten en specifieke eigenschappen van LA van verschillende oorsprong
worden onderzocht. Een doel van de studie is om te zien of LA kan gebruikt worden als diagnostisch
criterium voor de exploratie naar verborgen en nog niet gediagnosticeerde HIV gevallen.
Deze studie is gebaseerd op de zoektocht in PubMed – database. Op basis van verschillende
sleutelwoorden en gerefereerde literatuur wordt er een literatuurselectie gemaakt. Een stage van 6
weken in Moskou (Rusland) leverde ook een extra bijdrage en beter inzicht van het probleem.
Tuberculose
(TB),
Nontuberculeuze
mycobacteriose
(NTB),
Cytomegaalvirus
(CMV)
en
Pneumocystis jirovecii (PJP) zijn gekend als de voornaamste oorzaken voor HIV geassocieerde LA.
Associatie van HIV met verschillende kwaadaardige aandoeningen, die LA als klinische presentatie
hebben, worden beschreven: Kaposi sarcoom (KS), Hodgkin lymphoom (HL) en bepaalde subtypes
van non-Hodgkin lymphoom, vooral het Burkitt lymphoom (BL).
Aan de hand van literatuuronderzoek wordt een beschrijving gegeven van belangrijke aandachtspunten
in de anamnese en het klinisch onderzoek die kunnen bijdragen tot een diagnosestelling van een HIV
infectie. Criteria voor een differentiaal diagnose tussen maligniteiten en infectieuse oorzaken van LA
worden geschetst. Persisterende en veralgemeende LA is nauw geassocieerd met HIV infectie en moet
de aandacht van iedere arts trekken op een mogelijke HIV infectie en vereist indien verdacht
aanvullende HIV-testen.
De incidentie van HIV was 2.3% in de groep van individuen met LA als een klinische presentatie.
Tot slot worden ook de situatie in Moskou met betrekking tot HIV behandeld en de innovaties
besproken gerelateerd met de behandeling van HIV geassocieerde lymfomen.
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2. Introduction
Since the discovery of the HIV in 1980s, the virus has extended its influence on the whole world. A
devastating effect on some regions and the impact that the virus has already made worldwide makes it
one of the greatest medical challenges of the 21st century. HIV has a high rate of spread and in our
modern world with global traveling and constant movement of the people, no country can declare
itself ‘free from HIV’.
The virus of HIV infects lymphocytes and during the progression of this chronic infection it has a
devastating effect on the immune system of the individual. The chronic progression of HIV infection
results in the acquired immunodeficiency syndrome (AIDS). Due to the fact that lymphocytes are the
target cells for the infection, the symptom of enlarged lymph nodes (LNs), lymphadenopathy (LA), is
one of the most common and consistent symptoms during the HIV infection. The aim of this study was
to provide a literature analysis on the association between the symptom of LA and progression of HIV.
LA is a symptom that can be found in every stage of HIV infection. Nevertheless LA is not a specific
symptom for HIV and it can be found in HIV negative individuals as result of various infections or
diseases. A special focus of this study was made on finding the particular associations between the
symptom of LA and HIV infection.
In general HIV positive individuals suffer from various infections in more progressive HIV. These
infections may lead to LA. The emphasis of our study was to identify and describe these particular,
distinctive infections that usually accompany HIV. The list of identified associated infections consists
of Tuberculosis (TB), Nontuberculous mycobacteriosis (NTB), Cytomegalovirus (CMV) and
Pneumocystis jirovecii (PJP). We describe them and put emphasis on the clinical features of LA in
these infections.
Another goal of the study is to determine specific malignancies that are associated with HIV and are
also responsible for the symptom of LA. Literature data search was made to identify and describe
these associated tumors. A closer look is taken on Kaposi sarcoma, Hodgkin lymphoma and Burkitt
lymphoma. The incidence of these malignancies in HIV positive individuals was compared to the
incidence in the general population. The clinical aspects of LA in the different associated infections
and malignancies were one of the major goals of this study.
The possibility of the detection of hidden HIV infections by means of LA as a diagnostic criterion was
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another focus of our literature study. The evaluation of the medical literature written about the
possibility of identification or suspicion of a hidden HIV infection with only basic clinical evaluation
(medical history, anamnesis and physical examination) was made.
The Russian experience on the subject of LA associated to HIV was also a priority of this study. Due
to the fact that most of the Russian data is published in Russian little of this information reaches the
western world. Exploration of the treatment modalities of HIV associated malignancies in Moscow
was made. Therefore a 6-week internship in medical institutions in Moscow, Russia took place.
3. Materials and methods
In this study the PubMed-database was used as a main source for the selection of relevant
publications. ‘Lymphadenopathy’, ‘lymphadenitis’ and ‘HIV’ terms and combination of an etiological
agent have been used as keywords for the ‘search’ option tool. Available articles were further preselected based on the relevancy, publication date and the impact factor of the journal. Further selection
was made based on information described in the publications with focus on most recent data.
Frequently the link ‘related articles’ was used as an additional tool. Similar selection criteria were
applied for the selection of relevant references.
The second main source for collection of relevant data were reference lists of pre-selected
publications. In this case authors names of chosen articles and/or terms indicated in a title were used in
a direct search in the Pub-Med database.
Again, one of the criteria for the search was the publication date. The most recent papers were
preferred but when an article was considered to present “crucial” findings, this was considered
sufficient for the selection.
As a rule of thumb the first and the last author’s names of the “crucial” articles were used as further
keywords to find more detailed information and recent results.
Textbooks and relevant internet sites were used to gather the basic, well-known data about the lymph
node structure, HIV and lymphadenopathy.
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4. Results
4.1. HIV virus
4.1.1. History and epidemiology
The first data related to the virus of human immunodeficiency (HIV), describing an abnormal
development of pneumocystic pneumonia and Kaposi sarcoma in male homosexuals were published in
1981 (Centers for disease control. Los Angeles 1981; Centers for disease control. New York 1981).
These studies described a few cases when patients suffering from pneumocystic pneumonia also
showed an additional abnormal symptom of a generalized LA. It was soon afterwards discovered that
the agent responsible for this remarkable disease was a retrovirus. In 1982 a new term was introduced:
acquired immune deficiency syndrome (AIDS). Since that time an enormous body of information on
HIV and AIDS has been collected.
HIV infection is a worldwide epidemic. According to the World Health Organization there is an
estimated 33.0 million of people living with HIV. This statistics are provided by the UNAIDS/WHO
report published in 2008 (Table 1).
Table 1: Global HIV/AIDS estimates, end of 2007
People living with HIV/AIDS
33.0 million
Adults living with HIV/AIDS
30.8 million
Women living with HIV/AIDS
15.5 million
Children living with HIV/AIDS
2.0 million
People newly infected with HIV
2.7 million
Children newly infected with HIV
0.37 million
AIDS deaths
2.0 million
Child AIDS deaths
0.27 million
4.1.2. Biology of the virus
According to Medical Microbiology (Mims et al., 2004), HIV is a member of the genus Lentivirus
belonging to Retroviridae family. Lentivirus means ‘slow’ virus and this name is given to the group
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due to the long interval between the initial infection and the onset of severe symptoms (Chiu et al.,
1985). Two genetically distinct viral types have been identified. HIV-1 which is present in Europe,
Asia, America and Central Africa and HIV-2 which is only situated in the Western Africa (Tebit et al.,
2007).
The virus is an enveloped RNA virus and is transmitted in single stranded, positive-sense ssRNA form.
After the transmission the reverse transcriptase, which is also present in the virus, transforms the
single-stranded RNA to a double-stranded DNA and then the virus DNA is integrated and transcribed
with help from the cellular system of the host. After such integration there are two possibilities: either
the virus becomes latent and the infected cells continue their function without any disturbance to the
host cells or the virus becomes active and starts to replicate itself. In the latent stage the HIV can be
‘sleeping’ for several years or even a decade. When a huge number of viruses are formed a cell
ruptures and lysis occurs resulting in the spread of the virus to the extracellular compartment (Potter et
al., 2007).
The process of the selection of target cells that are infected by HIV is based on the recognition of CD4
receptors on the host cells’ surface by the virus. The cells that have such CD4 receptors on their cell
surface are T-lymphocytes, monocytes, dendritic cells and microglia. T-lymphocytes have one of a
crucial function of the immune system in the recognition of infectious agents; they are called CD4 ‘Thelper’ cells. The activation of CD4 ‘T-helper’ cells takes place as a response of the immune system to
various microbial agents. When these cells are in the naïve state no replication of HIV takes place,
only when the T-lymphocytes are activated the HIV may proceed with the replication (Mims et al.
2004).
The main function of the CD4 ‘T-helper’ cells is activation of other cells of the immune system such
as B-lymphocytes and cytotoxic T cells (Fahey et al., 1990). An abnormal activation of the immune
system has been shown to be a major factor in the disease progression. A pool of activated CD4 Tcells is formed that can be targeted by HIV and this may lead to the exhaustion of the immune system
(Potter et al., 2007).
There are four ways of the virus transmission: sex, blood contact (contaminated needles), breast milk
and transmission from an infected mother to her child at birth. The majority of HIV infections are
acquired through unsafe sex. A contact between infected sexual secretions from one partner with oral,
genital or rectal mucous from another partner is required for this way of transmission. The dendritic
cells swallow the virus particle and bring it across the mucosa to the lymphatic system, to the lymph
node (Lekkerkerker et al., 2006).
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Contaminated needles are responsible for the transmission in the population of intravenous drug users
and hemophiliacs. This form of transmission is also seen in blood transfusions when the donor blood
was not adequately checked for the virus. Breast-feeding, in utero transfer and transmission during
childbirth are responsible for the vertical transmission. HIV infection has four stages: it begins with
an incubation period that is followed by an acute infection, latency stage and AIDS (Boily et al.,
2009).
4.1.3. Treatment of HIV
Currently highly active antiretroviral therapy (HAART) is a common treatment applied to HIV
infected patients (Commented Drug Repertorium, 2010). HAART is aggressive treatment that is given
to suppress the viral replication, to delay and slowdown the evolution of the infection. The treatment is
given in function of the viral load and the CD4 count.
As a rule several types of medications such as: nucleoside reverse transcriptase inhibitors (NRTIs),
protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are prescribed. If
the drugs are administered one at a time there is a great chance for the resistance therefore the drugs
are given in association. One of the keys to success of the therapy and low incidence of resistance is a
good compliance of the patient. The percentage of the resistance that develops due to low compliance
is high.
Long-term effects of HAART are not yet known. The treatment is also given in prevention as
prophylaxis when there is a great risk for contamination or after an accidental exposure.
A regular therapy consists of an association of two NRTIs and PI or two NRTIs and NNRTI.
Since the introduction of HAART there have been significant changes in the frequencies of the HIVassociated diseases. The incidence of opportunistic infections has decreased significantly along with
the incidence of Kaposi sarcoma and non-Hodgkin lymphomas. Paradoxically an increase of the
Hodgkin lymphomas has been observed. The introduction of HAART has not only changed the
spectrum of the associated disease but also decreased the mortality, particularly malignancy
(Commented Drug Repertorium, 2010), (World Health Organization, 2009).
4.2. Lymphatic system and lymph nodes: structure and function
The lymphatic system is a well-organized network that is formed by functionally interrelated
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lymphoid tissue, and transportation pathways of tissue fluid/lymph and lymphoid cells. It consists of
different cellular components, lymphatic vessels and fluids. The most common cells of the lymph are
the CD4 T-lymphocytes and antigen presenting cells (APCs) such as dendritic cells and macrophages.
The organized lymphoid tissues form small rounded or oval shaped masses: the lymph nodes (LNs)
(Olszewski, 2003).
A LN has a bean form shape and is under normal conditions not larger than one centimeter. (Angeli
and Randolph, 2006) There are approximately 600 LNs in our body and they are commonly localized
in the base of all of the extremities, near to big blood vessels and are also situated in different groups.
The main groups that can be distinguished are the LNs in cervical, submandibular, axillary,
mediastinal, retroperitoneal and inguinal regions (Greer et al., 11th edition).
A closer look on the structure of the LN reveals an inner parenchyma that is surrounded by a capsule
of a connective tissue. This fibrous capsule penetrates the parenchyma and forms a fibrous supporting
meshwork. Further two histological regions of the parenchyma can be distinguished: a peripherally
situated cortex and a central medulla. Through the hilus blood vessels enter and leave the lymph node
(Greer et al., 11th edition).
Two main functions of the whole lymphatic system are the maintenance of fluid balance and
extravascular homeostasis and the formation of an immunological barrier system. It is in the lymph
node that a first encounter between an APC and a lymphocyte takes place. When a pathogenic
organism, for example a virus, is located in the peripheral organs or tissues an immunological answer
is induced. APCs such as dendritic cells or macrophages phagocytate or swallow up the pathogenic
particle and bring it through the system of lymphatic vessels to a LN. This particular LN is the most
proximal one that is found in the draining pathway of the lymph. After entering the LN APC interacts
with naïve, not activated T-cells, presenting it with the pathogenic particle. An activation of the T-cell
then takes place (Olszewski, 2003).
4.3. Phases of HIV infection and changes in the lymph node morphology
After intensive studies and research that has proceeded for two and a half decades enormous body of
information concerning HIV biology was gathered. The fact that the spread of the infection is so
rapidly progressing made a great impact on the amount of studies that were dedicated to uncover the
pathology and the anatomy of the virus. Now the dynamics of the HIV infection and its impact on the
immune system is relatively well understood (Klimas et al., 2008).
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It was found that HIV has a strong tropism for lymphoid tissues. Basically the virus infects the target
cells that have certain cell surface molecules one of which is CD4. The virus attaches itself to a CD4
receptor and a coreceptor and then penetrates the cell (Klimas et al., 2008).
After the infection an incubational period of several weeks takes place. At this stage the patient does
not have any symptoms of the infection.
•
Acute phase
On average an acute phase has a duration of 28 days, but the symptoms last normally for a week.
The viral load is the amount of viruses that can be found in the peripheral blood. This is a result of a
fast replication specific to the acute stage of the infection hence viral particles can be found in the
blood in abundance.
The virus migrates to the lymph nodes and causes reactive lymphadenitis. Along with the enlargement
of the lymph nodes symptoms of fever, rash, myalgia, pharyngitis, hepatomegaly, splenomegaly and
malaise are also frequent. Patients can also complain about headache, nausea and weight loss. These
symptoms basically lack specificity so it is a challenge to diagnose HIV at this stage of the infection.
An acute phase of the infection is highly contagious and patients should be prevented from spreading
the infection so an early diagnosis is very important (Levy, 2006).
At this stage of the HIV-infection enlarged lymphoid follicles with reactive germinal centers
characterize the structure of LN. There are aggregates of small lymphocytes that can focally penetrate
into the germinal centers and make their contribution to the follicle lysis and the destruction of the
germinal center (Caponetti and Pantanowitz , 2008).
•
Latent phase
It is hard to estimate the normal duration of this phase because it can vary from several weeks to a
decade and has therefore a very diverse length.
The phase of the virus latency is marked by a decrease in the viral load, so a fairly low amount of the
virus is present in the peripheral blood. However, large amount of the virus are localized in the
follicular dendritic cell network of the LN. Also depletion in the amount of the lymphocytes,
accumulation of plasma cells and the progressive involution of the germinal centers are specific
changes of the LN structure and morphology for this stage of HIV infection. The depletion of the
lymphocytes results in the drop of the amount of CD4 cells from normal levels of 1000 to 1400 cells
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per µl to several hundreds (Caponetti and Pantanowitz , 2008).
When the amount of CD4 drops below 500 cells per µl holes in the immune system begin to appear.
Patients begin to suffer from minor, yet not threatening infections like condylomas, fungal infections,
herpes simplex, thrush and vaginal candidiasis (Centers for Disease Control and Prevention. 1993).
•
AIDS phase
It is stated that when the number of cells drops under the level of 200 cells per µl acquired immune
deficiency syndrome (AIDS) develops. AIDS is a complex of well-known disorders that are normally
associated with low number of CD4 cells. At this stage of the infection patients begin to suffer from
serious infections such as Pneumocystis jirovecii (PJP), cytomegalovirus (CMV), toxoplasmosis,
infections of the eye and the intestine. Also weight loss is observed and HIV dementia can occur. At
this stage of the infection specific cancers, Kaposi sarcomas and lymphomas, form a threat to the
severely immunosuppressed patients (Centers for Disease Control and Prevention. 1993).
The progression of the infection has also a great impact on the morphology of LN. Follicles in the LN
become small or are already totally absent and have hyalinized ‘burnt-out’ germinal centers. In the LN
there is also depletion in the lymphocytes but the amount of plasma cells is increased (Caponetti and
Pantanowitz, 2008).
To conclude it should be underlined that the LN structure undergoes a progressive remodeling through
out the HIV infection that eventually results in the damage of the normal immune system. The finding
and identification of the morphological changes in the LN can therefore be diagnostical for the stage
of the infection and the material for such an evaluation can be acquired with fine needle aspiration
(FNA) or an open biopsy. It has to be mentioned that HAART treatment is associated with immune
reconstitution so the morphological patterns can be altered in patients who underwent such a treatment
(Caponetti and Pantanowitz, 2008).
4.4. Lymphadenopathy the main symptom of HIV infection
Lymphadenopathy (LA) is usually translated as a ‘lymph gland disease’. Typically the affected lymph
nodes are swollen so the meaning of this definition has transformed to ‘the enlarged lymph nodes’. So
LA is an enlargement of the LNs of more than 2 cm and this symptom must be present for at least 3
months in two or more LNs. However the term LA refers to the lymph nodes that are abnormal not
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only in size, but also in consistency, location and mobility.
A simple and clinically useful system of classification of LA is to identify localized LA and the
generalized LA. The localized LA is when lymph nodes are abnormal only in one region of the body.
The generalized LA can be stated when the lymph nodes are enlarged or abnormal in two or more
noncontiguous areas. The generalized LA is an indication that a systemic disease is present, so further
investigation is therefore necessary. Distinguishing between the localized and the generalized
lymphadenopathy is a very important step in the evaluation of a patient and helps to determine the
differential diagnosis (Ferrer, 1998)..
Lymphadenopathy is frequently a symptom deriving from an obvious cause, but in some cases, when
the root of the abnormal lymph node or lymph node group is less clear further diagnostic investigation
should take place. It is a diagnostical challenge to be able to distinguish between a self-limiting LA
and a LA that is caused by a serious disease (Ferrer, 1998).
The majority of localized lymph nodes are seen in the head and neck region, less in inguinal region
and seldom in axillary lymph node groups. A supraclavicular localized LA is frequently identified as a
malignant enlargement so further investigation of this type of localized LA is essential. Basically
when a localized LA is identified further physical examination becomes crucial not to miss a
generalized LA and to be able to diagnose the abnormal lymph nodes in other regions of the body
(Ferrer, 1998).
Due to the fact that the generalized LA is an indication of a systemic disease a biopsy is an absolute
necessity when the reason for the LA is not clear after the initial evaluation. The biopsy should be
made on the most abnormal and preferably the largest LN and not on the LN that is most accessible.
Patients with unexplained localized LA who have constitutional symptoms or signs, risk factors for
malignancy or LA that persists for 3 or 4 weeks should also undergo a biopsy (Ferrer, 1998).
Lymphoadenopathy is one of the profound and persistent signs during the progression of the HIV
infection. The HIV virus infects primarily the CD4 lymphocytes therefore the lymph nodes are
commonly involved during all the stages of the infection. LA is also one of the first, earliest symptoms
and signs of the HIV infection. It is seen among other general symptoms typical for a retrovirus
infection and is associated with a change in peripheral blood counts, a lymphocytosis (Ferrer, 1998).
The syndrome of ‘persistent generalized lymphadenopathy’ was described as one of the first
symptoms of HIV infections. This type of LA is present throughout the life of the patient. The
swelling in atypical areas is regularly present such as supracondylar and submandibular regions. This
is usually accompanied with symptoms of fever with night sweats, malaise, weight loss of more than
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10% in 6 months and diarrhea. Therefore LA is the most consistent symptom of HIV infection
throughout the progression of the clinical course (Ferrer, 1998).
There are various types of LN abnormalities in HIV positive patients: reactive lymphadenitis,
granulomatous lymphadenitis, with a further division to tuberculous and nontuberculous subtype,
pyogenic lymphadenitis and fungal lymphadenitis, also malignancies are regularly seen such as
Kaposi sarcoma Hodgkin, non-Hodgkin lymphomas, carcinomas and metastasizes (Gill et al., 2007).
Fine needle aspiration (FNA) cytology is an important technique of the LN biopsy. This method is
cost-effective, with a fairly low risk and provides a rapid diagnosis. Studies have shown that FNA
cytology has an established role in the differential diagnosis of infection, persistent generalized
lymphadenopathy and malignancy in HIV-infected patients. Lowe and colleagues describe a study on
62 HIV-positive patients. The total amount of FNA cytology procedures was 73 and different LNgroups were investigated: axillary (17%), cervical and supraclavicular (29%), inguinal (15%) and
other (2%). The most common diagnosis was persistent generalized LA (50%) followed by infection
(22%) and malignancy (18%); inflammation (10%) was also observed (Lowe et al., 2008).
An Indian study also performed a study on FNA cytology of the LN. Their goal of the research was to
evaluate FNA as a guiding tool to diagnose the etiology of the LA. They also tried to find out if this
method was useful in finding undiagnosed HIV positive cases with already a present symptom of
persisting LA. The research was made on 1082 LA cases and the incidence discovered and previously
undiagnosed HIV positivity was 2,3%. People with an undiagnosed HIV are unaware of their infection
and are transmitting the virus further. So a diagnosis of HIV is crucial and clinicians should always
keep a possibility of HIV positivity in mind when they encounter patients with unexplained and
persistent LA (Gill et al., 2007).
4.5. Physical examination of the patient with lymphadenopathy: how to
examine and what to look for?
A clinical practitioner that encounters a lymphadenopathy should make a detailed anamnesis of the
patient’s medical history and interrogate him/her about present symptoms, complaints and the
progression of LA.
A paper written by Ferrer describes the evaluation procedure of a patient with LA that will help to
gather all the information that is needed to form a correct differential diagnosis. The questions that
should be asked and the way a patient has to be examined are taken from Ferrer’s review work (Ferrer,
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1998).
Ferrer suggests that the interrogation has to include 4 essential key points:
•
Are the localized symptoms related to a specific site?
•
Does the patient have any constitutional symptoms such as fatigue, weight loss, fever or night
sweats
•
Epidemiological clues should be explored, such as travel history or risk behavior
•
Patient has to be asked if there is a medication intake that can on itself be a reason for LA
(Allopurinol, Atenolol, Carbamazepine, Cephalosporins, Penicillin, Sulphonamides, etc.)
Other questions that could be asked are:
•
Does the patient feel ill?
•
What was the speed of the onset of LA? Did it appear in several hours or days or has it been
slowly developing during several months?
•
How long has the lymph node been noticeably enlarged?
•
Are the nodes painful?
•
Recent viral illness or is somebody from the surroundings diagnosed with a viral infection?
•
Was there a TB exposure?
•
Are there any pets around?
•
Is there a habit of eating raw vegetables or meat?
•
Were there previous infections suggestive of an immunologic deficiency?
•
Family antecedents
Physical examination
After a detailed anamnesis and medical history of the patient a careful physical examination should
follow. Special attention should be given to the lymph nodes. Characteristics of the enlarged lymph
node have to be carefully examined. It is very important to estimate the size and the consistency of the
nodes. When an evaluation of a localized LA takes place a careful examination of the region from
which the lymph drains to this particular LN has to be made. Attention should be given to identify
the presence of skin lesions, evidence of infection or inflammation and the tumors. Careful
examination of the whole body has to be made to be able to exclude the generalized LA with the
presence of abnormal lymph nodes in the other regions of the body. Each examination should include
a careful palpation of anterior and posterior cervical LN, submandibular, axillary and inguinal lymph
nodes.
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When a lymph node is detected, the following characteristics have to be estimated: size,
pain/tenderness, consistency, matting and location.
•
Size
A normal lymph node has a maximum size of less than one centimeter, so every node that is larger
should be marked as abnormal. Some say that a distinction in the location has an impact on the size of
abnormality and that inguinal nodes should be considered abnormally enlarged when there size is
greater then 1.5 cm, whereas epitrochlear nodes have a lower level of abnormality namely 0.5 cm.
Size of the lymph node has not much of specific information for the diagnosis of a particular cause,
however there is a direct relationship between the size and the possibility for a cancer.
•
Pain and tenderness
When a lymph node enlarges a stretch of its capsule can be a cause of pain. Pain is usually associated
with an inflammation or suppuration, but can also be as a result of the hemorrhage into a necrotic
center of a malignant node. Tenderness is not reliable for a differentiation between a benign and
malign cause of LA.
•
Consistency
The consistency of the abnormal lymph nodes is very various, therefore helpful in the narrowing of the
differential diagnosis. A firm but rubbery consistency is suggestive for a lymphoma. A softer LN is
more characteristic in an infectious or inflammatory condition. Suppurant nodes can be fluctuant.
When a stone-hard lymph node is found it is typical indication for a malignancy, metastasis of a
cancer.
•
Matting
When a group of lymph nodes feels to be connected or seem to be moving as a unit, these LN are
called ‘matted’. Matted LN can be present in benign situation such as TB or sarcoidosis or in
malignant circumstances for instance lymphoma or cancer metastasis.
•
Location
Anatomical location of the abnormal lymph nodes is very important in differential diagnosis.
Careful examination of the head and neck reveals the most common cause of the swelling, the
enlarged cervical lymph nodes. A doctor should stand behind the seated patient and be methodically
14
palpating the anatomical areas of the neck. If there is a presence of cervical adenopathy further
examination has to take place to detect a local cause, for example an infection, ear, nose and throat
inspection is also indicated.
The axillary lymph nodes are examined with the patient lying on the back and the examinator using
the right hand to palpate the left axillae and left hand for a right axillae palpation. Several groups of
the nodes are identified in the axillae: medial, lateral, posterior, central and apical groups.
Inguinal nodes are easily examined when the abdomen investigation is performed. Confusion between
an enlarged inguinal LN and irreducible femoral hernia can take place. When inguinal LNs are
enlarged they may cause an abnormal fullness of the central abdomen when it is palpated.
A supraclavicular LN enlargement is frequently associated with a malignancy. A Valsalva's maneuver
performed by a patient during palpation of the supraclavicular fossa increases the chance of detecting
of supraclaviculair LN. For this group of LN another parameter should also be taken into account – the
right or left location. The drainage of the lymphatic flow from thorax and abdomen is associated with
the left supraclavicular node, the Virchow’s node, so the enlargement can be a signal of testicular,
ovarian, pancreas, kidney, prostate, stomach or gallbladder pathology. The right supraclavicular LA is
associated with a malignancy of mediastinum, lungs or oesophagus.
When generalized LA is present, signs of systemic illness have to be carefully evaluated. The
identification of rash, mucous membrane lesions, hepatomegaly and splenomegaly, arthritis can be
helpful. The enlargement of liver and milt, hepato and splenomegaly, is seen in many conditions
including mononucleosis-like syndrome, lymphoma or sarcoidosis.
Detailed and careful clinical history of the patient and a physical examination will as a rule help to
identify the easily diagnosable reasons for a LA such as upper respiratory tract infection, pharyngitis,
periodontal disease, conjunctivitis, lymphadenitis, insect bites, recent immunization, cat-scratch
disease or dermatitis, and no further assessment is necessary.
If the clinical history and examination are suggestive for a particular disease, a number of specific
tests that will verify the diagnosis have to be applied. If the tests results give a positive conclusion,
treatment can be started.
Unexplained LA is diagnosed when the cause is not identified after the initial evaluation or when the
presumptive diagnosis is not confirmed with the tests or by clinical course. Specific tests are necessary
in the case of generalized LA because it is an indication of the presence of systemic disease, therefore
further testing has to be made. A biopsy of the LN has to be performed from the largest and the most
15
abnormal of the LN and not from the one that is most accessible. Localized unexplained LA has to
undergo a biopsy if there is a worrisome clinical picture or the presence of constitutional symptoms.
Biopsy is preferred over a fine needle aspiration of the cells because of its lower risk for the ‘seeding’
of possible malignant cells and therefore danger for metastasis, another reason for the biopsy is the
preserved architecture of the lymph node which has extra diagnostic information. If malignancy is
suspected, the obtained material may be further explored by histological examination, flow cytometry,
genetic research and breeding on special medias. The molecular investigation on fresh material can
also be made.
The blood tests have to be made and several parameters are crucial for the differential diagnosis. A
total white blood count should be made with a differentiation of the leukocytes. If any reactive
lymphocytes are present they should be recognized and their quantity measured. Further the levels of
C- Reactive Protein (CRP) and Lactate Dehydrogenase (LDH) have to be evaluated and erythrocytes
sedimentation rate (ESR) measured. CRP and ESR are used as markers of the inflammation.
An echo of the lymph node is important along with an echo of abdomen and RX of the thorax. More
accurate information about the lymph node enlargement, the position and the consistency can be
achieved by using ultrasound.
In some cases computer tomography (CT-scan) along with Positron Emission Tomography (PET-CT)
and Magnetic resonance imaging (MRI) are used.
It should be also pointed out that not all the swellings are from the lymph nodes. Other reasons for an
enlargement should be distinguished such as lymphangioma’s and haemangioma’s, primary tumors,
cysts, etc.
Enlargement of the lymph nodes that persists for at least three months in at least two extrainguinal
sites is defined as persistent generalized lymphadenopathy and is common in patients in the early
stages of HIV infection. Other causes of generalized lymphadenopathy in HIV-infected patients
include Kaposi's sarcoma, CMV, toxoplasmosis, tuberculosis, cryptococcosis, syphilis and lymphoma
(Ferrer 1998; Howard and Hamilton, 2007).
4.6. Lymphadenopathy in HIV-positive patients as a result of opportunistic
infections
During the progression of HIV infection weakening and deterioration of the immune system slowly
16
takes place. The number of CD4 cells declines making the patient vulnerable and susceptible to
various infections, especially opportunistic infections.
When a patient still has the an amount of 600 or more per µl CD4 cells, the immune system remains
protective enough against opportunistic infections. But when the counts of CD4 further decline and
reach a number of fewer than 350 cells per µl the immune system is becoming to be impaired and risk
for associated infections increases. When the AIDS phase is reached there is an imminent risk and the
infection can lead to serious complications (Ong, 2008).
In this thesis the relation between HIV and the following infections will be described: Tuberculosis
(TB),
Nontuberculous
mycobacteriosis,
Cytomegalovirus,
Pneumocystis
jirovecii,
Fungi,
Toxoplasmosis, Mycoplasmosis, Cryptococcosis and Clastridiosis.
4.6.1. HIV-LA in tuberculosis
TB is caused by Mycobacterium tuberculosis and the infection is spread by airborne transmission.
This is an efficient way of transmission given that infected people spread an enormous amount of
mycobacteria by coughing. The waxy coat of mycobacterium allows it to endure drying so it can
survive in air for a sufficient period of time. After the inhalation of M. tuberculosis it is phagocytosed
by alveolar macrophages in which M. tuberculosis survives and even multiplies. It is then transported
to a lymph node where a cell-mediated immune response is triggered. If 4-6 weeks after the infection
a purified protein derivate of M. tuberculosis is introduced into the skin, an infection is detectable by a
local induration and eryhtema 2-3 days later. To prevent a general infection lymphokines are released
that activate the macrophages and increase their ability to destroy the mycobacteria. Activated T cells
are responsible for the release of these lymphokines. Tubercles are small granulomas containing
epithelioid cells and giant cells. These pulmonary lesions together with activated lymph nodes are
called the primary complex. Perfectly healthy people may have tubercles that are fibrotic or calcified
which remain after a primary infection; they are detected with chest radiography as radio-opaque
nodules. In immunocompromised patients the mycobacteria are not contained within the tubercles and
they may cause a disseminated disease through the invasion of the bloodstream, leading to miliary
tuberculosis (Mendelson, 2007)
If a reactivation of ‘sleeping’ mycobacteria occurs, secondary tuberculosis is observed. This usually
happens when the patient’s immune system is weakened by the progressing HIV infection.
The clinical presentation of tuberculosis with HIV is associated with the symptoms of cough, fever
17
present for a period of time longer than 2-4 weeks, diarrhea, weight loss (more than 20% body weight
or more than 10kg), oral thrust, haemoptysis, history of herpes zoster and lymphadenopathy (Huang
and Crothers, 2009).
Extrapulmonary tuberculosis and mycobacteremia becomes more common as is frequently seen when
the level of the immunosuppression increases and HIV-infection progresses. When in HIV-positive
patients fever is encountered which cannot be explained and which persists for a fairly long time,
diagnosis of extrapulmonary tuberculosis has to be excluded. The clinical presentations of abdominal
TB are the visceral lesions and intra-abdominal LA that can be visualized by a computed tomography
(Jones et al., 1993).
Mediastinal adenopathy is a very common symptom in AIDS patients. However, a molecular typing
of isolates from HIV positive patients with a primary or reactivated TB showed that mediastinal
adenopathy was not a direct indication of primary TB. It reflects an ineffective immune system
response and can therefore become a result of reactivation of the previously acquired TB (Jones et al.,
1997).
HIV and tuberculosis in Russia and Eastern Europe:
According to the report by C.K Vorkas and C. van der Horst dating from November of 2009 there is a
12.3% prevalence of multi-drug-resistant tuberculosis in Eastern Europe. The cumulative mortality of
HIV/TB is also elevated in Eastern Europe in comparison with the rest of the world and is 33%. The
authors report that only 44.5% of the patients have been treated with the recommended regimens
(isoniazid, rifampicin and pyrizinamide). The situation is considered to be alarming and the effects of
HIV-TB epidemics are predicted to be devastating (Vorkas and van der Horst, 2009).
•
IRIS
When HAART is given for the first time to patients with a profound immunosuppression and low
counts of CD4 cells, an immune Reconstitution Inflammatory Syndrome (IRIS) may occur. IRIS is
described as a deregulated and excessive inflammatory answer, which is directed to the antigens of
opportunistic infections and has an influence on the course and clinical presentations of the disease. It
has been estimated that the level of immunosuppression is directly proportional to the appearance of
IRIS. According to the WHO report, HAART is frequently given only at the stage of low CD4 counts
in developing countries and this may result in a higher prevalence of IRIS.
There are two forms of IRIS. The first one reveals an acute opportunistic infection. The second one is
a “paradoxical” form. It is seen when the patient was already diagnosed with an opportunistic infection
18
and received a correct treatment with response to the therapy and therefore shows sterile microbiologic
cultures. After the administration of HAART a clinical deterioration is seen, the recurrence of the
symptoms of opportunistic infections occurs and inflammatory manifestations in one or more organ
systems are observed. In such a clinical condition it is obvious that alternative causes of deterioration
should be excluded.
The problem of a heterogeneous presentation of opportunistic infections in HIV positive patients
with variable immunopathological mechanisms in patients receiving HAART makes it difficult for a
clinical practitioner to diagnose with certainty the immune reconstitution inflammatory syndrome.
Basically, on its own IRIS has a wide range of clinical presentations. Therefore it is difficult to assess
the contribution of excessive inflammation to the presentation of the illness
IRIS is seen in association with TB, CMV, Cryptococcus neoformans, Mycobacterium avium complex,
PJP, Kaposi sarcoma, non-Hodgkin lymphoma and other diseases (Davies and Meintjes, 2009).
4.6.2. HIV-LA in nontuberculous mycobacteriosis
Nontuberculous mycobacteria (NTM) refer to all the species in the family of mycobacteria that may
cause human disease, but do not cause tuberculosis (TB). There are more than 130 species known and
the infection occurs when a contact with the infected, contaminated environment takes place. Most
species of NTM have no pathogenic effect on humans but in the conditions of immunosuppression
predisposing conditions may lead to opportunistic infection. The species are divided in slow and rapid
growers, slow growers normally are responsible for pulmonary and lymphonodal disease and rapid
growers affect cutis, bones and joints (Tortoli, 2009).
Infections of the lymph nodes
In infantile cases a unilateral cervical lymph node swelling is usually observed. The swelling is
painless, sometimes has fistulas and has a variation in size between different patients. Usually a
surgical excision is needed because anti-microbial treatment is ineffective (Tortoli, 2009).
IRIS with a reaction of bilateral superficial and deep lymph nodes can take place. This paradoxical
immune reaction to pre-existing undiagnosed opportunistic infections happens after the administration
of HAART and as a result of the restoration of immune system.
The species responsible for the pulmonary infection is Mycobacterium avium complex (MAC) with its
19
two major species M. avium and M. intracellulare. Normally patients with this type of pulmonary
infection are severely immunocompromised with counts of CD4 under 100 cells per µl but after the
introduction of HAART the number of the patients with MAC declined considerably (Tortoli, 2009).
In AIDS patients the most frequent symptoms are cough, fever and rapid weight loss. RX of the thorax
shows mediastinal or hilar adenopathy and the progression is very rapid.
A few weeks after the infection granulomatous lesions of cutis and soft tissues develop. The infection
spreads and involves satellite lymph nodes that can evolve to ulceration, cellulitis and cutaneous
dissemination. This type of infection is normally transmitted by a direct contact with infected water or
fish, trauma or surgical wounds. The HIV patients are mostly infected by Mycobacterium
haemophilum that results in painful soft tissue abscesses and often relapses. This particular specimen
is often undiagnosed because of its strict growth requirements (Tortoli, 2009).
•
Disseminated Mycobacterium avium complex (MAC) infection
This is the first opportunistic infection that was detected in AIDS patients. It is thought to be the most
common bacterial opportunistic infection in adults with HIV- 1 virus in the western world with an
annual frequency of 10-20% at the AIDS stage of the disease. Another study report showed that
around 50% of all the patients with CD 4 counts lower than 100 cells per µl have MAC.
A retrospective cohort study of 2081 HIV positive adults showed that MAC was associated with
elevated mortality independent of the CD4 counts. This is suggested because the disease is a marker of
immune system failure and the disseminated infection gives an additional effect on morbidity (Moore
and Chaisson 1996).
The survival period of disseminated MAC was very short (average of 120 days) before the
development of specific combinational therapies and HAART. A huge breakthrough was made with
the introduction of HAART that allows maintaining the CD4 counts above the risk level (more than
100 cells per µl) and this makes the disseminated MAC quite rare in HIV infected patients today.
Nevertheless patients with a profound immune suppression continue to be at risk for disseminated
MAC. Basically HAART has a primary prevention effect rather than increase of survival after the
diagnosis with disseminated MAC.
The infection is spread via local lymphatics and haematogeneously. The bacteria are phagocytosed by
mononuclear cells and spread throughout the body in liver, spleen and bone marrow.
Mixed infections with other NTM are reported and a large number of other NTM species is also
responsible for disseminated infections in AIDS patients.
20
Apart from lymphadenopathy the clinical presentations of MAC are: fever, weight loss, fatigue,
anemia, night sweats, abdominal pain, diarrhea, hepatomegaly and splenomegaly. The problem for a
clinician is that these symptoms lack specificity and can be associated with other opportunistic
infection or malignancy common in HIV-association (Karakousis et al., 2004). It has been shown in a
number of case-control studies that patient with AIDS and disseminated MAC are more likely to have
systemic symptoms such as fever, night sweats, respiratory and gastrointestinal symptoms, elevated
values of alkaline phosphatase and lactate dehydrogenase, and reduced levels of hemoglobin (Gordin
et al., 1997; Rolla et al., 1999). These systemic symptoms mimic disseminated TB infection and it is
not simple to discriminate between these two entities. Factors that are most commonly seen in
disseminated TB are night sweats, peripheral LA, acid-bacilli smears of the sputum, chest RX with
hilar enlargement and the absence of previous AIDS illness. Factors more associated with MAC are
hepatomegaly, splenomegaly, leucopenia, elevated levels of alkaline phosphatase of more than twice
the normal levels, and elevated serum γ-glutamyl transpeptidase of more than 3 times of the normal
(Hsieh et al., 1998).
4.6.3. HIV-LA in cytomegalovirus
CMV is the largest human herpesvirus, has only one serotype and is transmitted by saliva, urine, blood,
semen and cervical secretions. This virus is responsible for the most frequent viral pneumonia seen in
HIV patients (Huang and Crothers, 2009).
After clinically silent infection in the upper respiratory tract, CMV spreads locally to lymphoid tissues
and then systemically in circulating lymphocytes and monocytes to involve lymph nodes and the
spleen. The virus inhibits T-cell responses, and there is a temporary reduction in their immune
reactivity to other antigens (Huang and Crothers, 2009).
The incidence of CMV disease in HIV-infected patients has declined sharply after the introduction of
HAART, however many are still at risk for CMV disease. According to the earlier studies there has
been an under-diagnosis of CMV in HIV – patients and frequently the diagnosis was made postmortem.
The two most frequent manifestations of CMV are retinitis and gastrointestinal disease. Retinitis is an
end-organ manifestation of CMV in HIV-positive patients. With the exception of retinitis the HIVpositive cytomegalovirus infection is very unspecific in the clinical characteristics. The clinical
presentation of CMV in HIV-positive patients does not differ much from HIV-negative patients, but
the progression of the disease is much more aggressive. The virus is often detected in bronchoalveolar
21
lavage in patients with an advanced immunosuppression when the evaluation for opportunistic
infections takes place. Basically the risk for CMV sharply increases when CD4 counts are below 100
cells per µl. Most cases of pneumonia are in patients with CD4 counts of less than 50 cells per µl
(Huang and Crothers, 2009).
The main symptoms of CMV are cough, fever and dyspnoea and are present for 2-4 weeks.
LA may be present but is not a common symptom. A study made by the group of Salomon et al
reports hilar and mediastinal adenopathy in 2 cases from 18 patients with HIV associated CMV
pneumonia (Salomon et al., 1997).
4.6.4. HIV-LA in/and Pneumocystis jirovecii
Pneumocystis jirovecii is the most frequent opportunistic infection to cause pneumonia in AIDS. (Fujii
et al., 2007) This genus is very successful in immunocompromised hosts. Pneumocystic organisms are
from the fungi group, however they seem to be atypical fungal microorganisms and are not able to
grow in vitro in fungal culture media. In AIDS patients frequently a co-infection with CMV has been
reported. (Fujii et al., 2007)
After the introduction of the combinational antiretroviral therapy, HAART, and the decline in AIDSassociated mortality the incidence of associated pneumonias has also changed.
Classical symptoms of PJP are fever, non-productive cough and dyspnoea. The onset of the symptoms
can be less acute in patients with a severe immunosuppression who already reached the AIDS phase in
comparison to the individuals with higher CD4 counts (Fujii et al., 2007).
Pneumocystosis with an extrapulmonary involvement is quite rare and seen in patients with a severe
immunosuppression. Lymphadenopathy of hilar and mediastinal lymph nodes is atypical (Ong, 2008).
There is not much literature written about the HIV associated LA in the cases with pneumocystosis.
4.6.5. Other opportunistic infections associated with HIV
A number of others opportunistic infections have an increased incidence of contamination of
immunosuppressed HIV positive individuals. As a rule these infections flourish when the counts of
CD4 T-lymphocytes are below 200 cells per µl in the AIDS phase. They can also be the reason to the
persisting LA that is specific to this terminal stage of the disease progression.
22
When the immune system begins to show a lack of its own function normal commensal
microorganisms begin to invade the body. Some species of fungi, Candida and Aspergillus, are
examples.
Candida is a normal commensal of the skin, gastrointestinal and genitourinary tract. When it succeeds
in the infection of the body it is then associated with a wide spectrum of diseases that are challenging
to diagnose because they do not show specific symptoms. Due to reduction of immune mucosal
function the opportunistic infections such as candidiasis have greater chance to infect and cause the
oral lesions. Oral lesion is a symptom that should make the doctor suspicious of severe
immunosuppression in a particular individual (Enoch et al., 2006).
Also Aspergillus cause very vague and non-specific symptoms in immunosuppressed individuals, so
even invasive Aspergillus may be asymptomatic (Enoch et al., 2006).
Protozoan parasites such as Toxoplasma are also observed as opportunistic infections in AIDS too.
Toxoplasmic encephalitis is the most commonly recognized cause of the central nervous system
disease in AIDS patients. At least 30% of patients with AIDS who have preexisting toxoplasma
antibodies will ultimately develop toxoplasmic encephalitis. A highly lethal syndrome of disseminated
toxoplasmosis, fever and sepsis-like syndrome with hypotension and disseminated intravascular
coagulation has been described in HIV-positive patients (Schmidt-Hieber et al., 2009).
Atypical bacteria such as Mycoplasma, which do not have a true cell wall, may also cause a lot of
problems for immunosuppressed individuals. Mycoplasma pneumonia usually manifests itself in
lower or upper respiratory tract, but extrapulmonary manifestations such as central nervous system are
common too (Waites et al., 2008).
Encapsulated round oval yeast, surrounded by a polysaccharide capsule, Cryptococcus neoformans,
with its two pathogenic subtypes is also a threat in HIV-positive patients. HIV-infected individuals
present with similar clinical features as immunocompetent patients, however they are more likely to
develop disseminated infection. The route of the infection is pulmonary via inhalation of infective
particles. In immunocompetent patients inhalation of yeast is followed by a localized immunological
response with a granulomatous reaction that contains the organism before symptoms of dissemination
occur; in immunocompromised dissemination is almost a rule and the subsequent blood spread can
involve any organ. The cryptococcal infection is also more likely to threat patients with a severe
immune suppression, such as patients in AIDS-stage of the disease with CD4 counts of less than 50
cells per µl. Cryptococcal infection may lead to meningitis or meningoencephalitis. In the era of
HAART the incidence of cryptococcal meningitis is dramatically reduced (Waters and Nelson, 2005).
23
4.7. Lymphadenopathy in HIV-positive patients as a result of malignancies
There is an association between a group of tumors and HIV-infection that results in a sufficiently
increased prevalence of the certain malignancies in HIV positive individuals. Different types of
malignancies are seen at different stages of the HIV–infection, and are therefore linked to the level of
the immunosuppression. The most common AIDS- associated cancers are Kaposi sarcoma and nonHodgkin lymphoma (NHL), their rates are increased after even a modest immune suppression.
Hodgkin lymphoma (HL) is also associated with HIV but it is more frequently seen when the immune
deficiency is more profound. There are also several unusual lymphoproliferaitve entities that have an
increased incidence in HIV positive cases: primary effusion lymphoma, Castleman’s disease, EBVassociated lymphoproliferaitve disorder, T-cell lymphomas and primary central nerve system
lymphoma (Navarro and Kaplan, 2007).
The risk for Kaposi sarcoma is increased by 1000-fold and the incidence is linked to a severe immune
deficiency and the increase of the risk has an exponential rate with a decline of CD4 counts, but
incidence is also elevated in patients with a moderate CD4 count decrease. After the introduction of
HAART a dramatic decrease in Kaposi sarcoma cases was observed and is now stabilized on the much
lower level than before HAART era, nevertheless this level is substantially higher in comparison with
a healthy population (Grogg et al., 2007).
NHL is increased about 70-fold in HIV patients. Different types of NHL have a different relationship
with the immunosuppression: diffuse large B cell lymphoma has an elevated incidence in patients with
a severe immune deficiency (50-100 CD4s per µl), Burkitt lymphoma occurs more frequently at any
stage of immune suppression and primary brain lymphoma is more likely to develop when the CD4
counts are less than 50 cells per µl. Clinical studies showed a decrease in the rate of NHL in patients
with advanced HIV after the introduction of HAART therapy. Most studies show a more limited
decrease in Burkitt lymphoma rates (Grogg et al., 2007).
HL is 10-fold higher in HIV patients. No decrease after the introduction of HAART has been reported
and two large United States studies have even reported an increase in the rate. HL rates are higher in
patients with a moderate immune deficiency than with more profound deficiencies (Grogg et al., 2007).
24
4.7.1. HIV-LA in Kaposi sarcoma
Kaposi sarcoma (KS) was for the first time described by Moritz Kaposi in 1872 (Kaposi, 1872).
Before the AIDS time it was a slowly progressing and rare tumor of low extremities that was mostly
seen in elderly man. The slow progression of the tumor resulted in a low rate of mortality. But in
1980’s an unusually high incidence of Kaposi sarcoma was seen in homosexual young males. Patients
were much younger than previously seen and the sarcoma was present in abnormal sites and had a
very aggressive progression. All these patients were positive for HIV (Centers for Disease Control,
1981).
Kaposi sarcoma associated virus (KSHV) is a human herpesvirus 8 (HHV-8). This HHV-8 virus is the
essential pathogenetic factor and was isolated from an HIV positive patient in 1994 (Chang et al.,
1994).
One of the most important differences between the HIV positive KS and HIV negative type is the
aggressive progression and the mortality rate of the disease. When the immunodeficiency is untreated
and is severe the mean survival time is very short and is not more than one year (Brockmeyer and
Barthel, 1998). The prevalence of the KS is also related to the grade of the immunosuppression. In pre
HAART era KS was occurred in 25% of homosexual man, this prevalence is not significantly lower at
5-7% in the same risk group (Rezza et al., 1999).
First clinical symptoms are red-brown plaques that grow into nodules and begin to ulcerate. These are
widespread lesions that are located preferably on the upper body (neck, trunk and arms). Plaque
lesions are often asymptomatic, can be single or multiple, are found in groups or can be widely spread.
In the progression of the disease the lesions become more numerous, they involve skin, oral mucosa,
lymph nodes and visceral organs (lungs, liver, spleen and gastrointestinal tract). The progression of
these plaques is an enlargement, they join together and evaluate to a nodule. Macular lesions, plaques
and nodular lesions are seen in oropharyngeus, lesions are spotted in gastrointestinal tract from
oesophagus till the rectum and anus. In 60% of the cases generalized lymphadenopathy is present.
Systemic symptoms such as fever, diarrhea, weight loss, malaise and fatigue may accompany the
disease. Progressive viral disease such as anogenital herpes, herpes simplex, herpes zoster and
cytomegalovirus are commonly observed (Potthoff and Brockmeyer, 2007).
To make the diagnosis of KS the following investigations should take place: a complete examination
of the skin and oral and genital mucosa, lymph nodes and abdominal ultrasound, chest X-ray. If there
25
is a mucosal involvement a gastroduodenoscopy and colonoscopy are necessary. A proliferation of
endothelial-like cells and fibroblasts are seen in the histology (Potthoff and Brockmeyer, 2007).
Immunohistochemistry is a standard method of KSHV identification. This method proved to be more
reliable than other diagnostic methods. For the recognition of Kaposi sarcoma monoclonal LANA-1
antibodies are used, it also allows to recognize the subtypes of Kaposi sarcoma lesions, is present in
the mantle zone of multicentric Castleman’s disease and KSHV- positive lymphomas.
PCR is an extremely sensitive technique but with a fairly high amount of false positive results coming
from contamination. This method of detection allows detecting and identifying KSHV in different
tissues and can be used on fresh or frozen material.
In situ hybridization is also a possible diagnostic method for KSHV.
Staging of HIV associated KS was introduced and it is based on the location and the degree of the
immunosuppression (Krown et al., 1989).
Table 2. Staging of HIV-associated Kaposi sarcoma (Krown et al., 1989).
T0
Tumor
T1
Immune
system
Tumor (macular) is limited to the skin, lymph node and hard palate
Visceral tumor, tumor-associated edema or ulceration or extensive
oral tumor (nodular)
I0
CD4 cells > 200 per µl
I1
CD4 cells ≤ 200 per µl
S0
Systemic
diseases
S1
No history of opportunistic infections or oral candidiasis, no
constitutional symptoms,
History of opportunistic infections, oral candidiasis or other HIVassociated diseases, constitutional symptoms
In the pre HAART era a treatment of a low dose of interferon had a poor result in patients with a
severe immunosuppression, when the AIDS phase was already established. If patients had a higher
amount of CD4 (>400 cells per µl) it gave a 45% of remission (Rasokat et al., 1989).
Nowadays chemotherapeutics, liposomal anthracyclines, are used as a monotherapy. This is the first
choice of treatment and induces a remission in 80% of the cases. Main side effects of this protocol are
26
neutropenia, nausea and palmoplantaire erythrodysesthesia. When local therapy is used such as
cryotherapy, laser or excision recurrence and reappearance of the lesions may happen.
KS is also a radiosensitive tumor so radiotherapy may be applied. 80-90% of individual lesions regress
after radiotherapy. Lymph nodes are treated with a total of 40Gy, which are divided in 5 times 2Gy per
week.
An increasing knowledge in the pathogenesis of KS allows developing new medication that will aim at
the specific targets for molecular therapy (Potthoff and Brockmeyer, 2007).
4.7.2. HIV-LA in Hodgkin lymphoma
Thomas Hodgkin described this lymphoma in 1832 when he saw 7 patients with generalized LA,
splenomegaly, high fever and cachexia. This disease had neither a relationship with an infection nor
was it a metastasis of another tumor but still it had a lethal outcome (Hodgkin, 1872).
Hodgkin lymphoma (HL) is a tumor of lymphatic tissue that has a characteristic morphological
substrate with gigantic poly-nucleus cells of Reed-Sternberg. The cells are localized in a particular cell
arrangement, which is made out of a mixture of tumor and non-tumor reactive cells (lymphocytes,
eosinophils, neutrophils, plasma cells) sometimes surrounded by collagen fibers.
The HIV-HL has a different pathological and histological picture compared to seronegatieve HL. HIVHL has a much more aggressive clinical behavior and presentation. This has a major negative effect on
the prognosis of the disease along with a necessity for a specific treatment. A different pathology
spectrum is also encountered. A more mixed cellularity is seen; there is lymphocyte depletion and a
larger proportion of neoplastic cells of Reed-Sternberg. An association with Epstein-Barr virus (EBV)
is mentioned in 90% of the cases. The EBV genomes are episomal and clonal and probably this
elevated frequency shows that it is a relevant factor in the pathogenesis of HIV-HL (Grogg et al.,
2007).
A study by Biggar and his group made an evaluation of 317428 persons with AIDS during 477368
person years (py’s) and found out that HL was had occurred in 173 cases (36.2 per 105 py’s). Also the
incidence was 53.7 per 105 py’s in patients with CD4 counts from 150-190 cells per µl in comparison
with 20.7 per 105 py’s when CD4 counts were fewer than 50 cells per µl. They suggest that there is a
lower incidence of HL in severe immunocompromised cases and that the incidence of HL is decreased
with declining CD4 counts. This can explain the paradoxical rise in the incidence of HL after the
27
introduction of HAART therapy (Biggar et al., 2006).
Staging
•
Stage I is involvement of a single lymph node region or single extralymphatic site
•
Stage II is involvement of two or more lymph node regions on the same side of the diaphragm
or of one lymph node region and a contiguous extralymphatic site
•
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may
include the spleen and/or limited contiguous extralymphatic organ or site
•
Stage IV is disseminated involvement of one or more extralymphatic organs.
Normally patients with HL present themselves with asymmetrical superficial lymph node enlargement
that is painless and non-tender. This lymph node is firm but rubbery. Normal it is located in the
cervical region (60-70%), but it can also be situated in axillary region (10-15%) or in the inguinal area
(6-12%). The enlarged LN may also be located retroperitoneal; it is then hard to discover such a LN
without a computer tomography or other visualization techniques. A spontaneous increase and
decrease in the size of the LN is possible. Mediastinal involvement is possible (6-11%) and it is a
feature of nodular sclerosing type. The LNs may become matted. A normal beginning is an
enlargement of the peripheral single LN and then a progression by contiguity with lymphatic system.
In 50% of the patients a splenomegaly is encountered but the size of the spleen enlargement is not
massive. Hepatomegaly is possible as well. A late complication of Hodgkin is a cutaneous
involvement. This is seen in 10% of the patients and is an unusual presentation as well as the
involvement of the organs, bone marrow, gastrointestinal system, lungs, spinal cord and the brain.
Other symptoms (B symptoms) typical for HL are fever, pruritis and profound night sweats. Some
patients complain that the areas where the lymphoma is present become painful after an intake of
small amounts of alcohol. Frequent symptom is a weigh loss and the feeling of weakness and fatigue.
There are indications of anorexia and cachexia (Hoffbrand et al., 2001).
28
Figure 1. HIV-positive patient with Hodgkin lymphoma. Photo is taken in Hospital №60 (Moscow,
Russia) by Prof. Dr. A.V. Pivnik
Figure 2. HIV-positive patient with Hodgkin lymphoma. Photo is taken in Hospital №60 (Moscow,
Russia) by Prof. Dr. A.V. Pivnik
29
A comparison between a HIV-HL that developed before the beginning and after of HAART therapy
was made. 84 patients were receiving HAART at least 6 months before the onset of HL and 206
patients received HAART only after the diagnosis of the HL. These patients were divided in 2 groups
and their results were compared. In the HAART pre-treated group B symptoms were less frequent,
higher leukocyte and neutrophils counts were registered. A better overall survival was associated with:
mixed cellularity, absence of extranodal involvement and B symptoms (Chimienti et al., 2008).
Another study had a similar investigation counting 104 HIV-HL patients and it reported that the
complete remission rates differ between the groups and that they were significantly higher in the
HAART pre-treated group (91% vs. 70%) (Berenguer et al., 2008).
4.7.3. HIV-LA in Burkitt lymphoma
BL is a distinct pathologic entity, a highly aggressive non-Hodgkin lymphoma, characterized by a
diffuse proliferation of small non-cleaved cells of B-lymphocyte origin. For the first time this tumor
was mentioned in 1897 in Uganda in black children aborigines with a tumor of facial skeleton, a ‘jaw
sarcoma’. In 1958 it was described and allocated by an English surgeon and traveler Denis Burkitt
(Burkitt, 1958). Later, in 1961, G.T.O’Conor has described a histologic picture of this tumor, having
characterized it as lymphoblastic lymphoma with low degree of a differentiation with great number of
histiocytes (O’Conor , 1961).
The incidence of the Burkitt lymphoma (BL) has had a giant increase after the HIV virus appearance.
If we compare the prevalence of non-Hodgkin’s lymphoma in the general population with the
prevalence of, this lymphoma in HIV positive patients we will find a significant difference with 1-2%
in the normal group and 35-40% in HIV- positive individual. (Spina et al., 1998). Burkitt’s lymphoma
is the second most common pathologic type of lymphoma encountered among patients with AIDS
(Levine, 2008).
Three types of Burkitt lymphoma are distinguished: endemic, sporadic and immunodeficiencyassociated type.
Endemic type: usually in black children aborigines of equatorial Africa and migrants from Africa to
New Guinea. The disease peak is 4-7 years with a considerable higher prevalence in boys compared to
girls (3:1) Approximately 95% of endemic Burkitt lymphoma is Epstein-Barr associated.
Sporadic type: typical morphology, immunophenotype and cytogenetics of Burkitt lymphoma revealed
in not endemic zone with characteristic clinical features. In the USA and Western Europe is the
occurrence of Burkitt in adults estimated to be approximately 1-2 % of all the lymphomas, with an age
30
median of 30 years. Children’s Burkitt lymphoma is responsible for 30-50 % of all lymphomas. Boys
are 2,5 times more likely to get the disease than girls. Unlike the endemic type, only 30 % of sporadic
Burkitt lymphoma is Epstein-Barr associated.
The immunodeficiency-associated type is found in 35-40 % of all HIV-associated lymphomas. An age
median: 35-40 years (addicts – 29 years, homosexuals – 37-42 years). The overwhelming majority are
men (up to 90 %). EBV is found in 30-40 % of cases. There is a geographical difference of this
association. In the western countries (USA, Europe) there is no Epstein-Barr but in Africa there is a
positive relation between EBV and immunodeficiency- associated type of Burkitt lymphoma (Bariakh
et al., 2009). It is frequently noted in patients with HIV infection with CD4 counts still exceeding the
200 cells per µl. No difference was found in the clinical characteristics of the patients with AIDS and
various levels of immune status with CD4 amounts lower and higher than 100 cells per µl (Spina et al.,
1998). A significant difference was found in the ‘median overall survival’ with BL between HIV
positive and negative cases and ‘disease free survival’ of 4 years was observed in 53% of HIV
negative and only in 7% of HIV positive patients (Spina et al., 1998). Also a difference in the
complete response rate that was defined as complete disappearance of all evaluable disease for at least
4 weeks was seen. The complete response rate in HIV positive individuals was seen in 40% compared
to 65% in HIV negative (Spina et al., 1998).
Generalized LA is one of the main symptoms for Burkitt lymphoma associated to immunodeficiency.
HIV-associated type of Burkitt lymphoma has a similar clinical progress as the sporadic type.
Typically there is extranodal involvement, abdominal localization of the tumor and peripheral lymph
nodes. Other symptoms are splenomegaly and invasion of the bone marrow happens in 30% of the
cases. The involvement of central nervous system is seen on average in 15% of the cases. The
histological picture does not differ from a non-HIV type (Bariakh et al., 2005).
The main symptoms that can be present are acute abdominal pains with nausea and vomiting, bowel
obstruction, gastrointestinal bleeding. Basically the symptoms can mimic acute appendicitis or
intussusception. Intra-abdominal presentation will usually affect intra-abdominal lymph nodes and the
bowel, however kidney, pancreas, breast or ovarian involvement is also possible. At the time of
diagnosis the size of the lymphoma frequently exceed 10 cm and this is called ‘bulky disease’ (Blum
et al., 2004).
Staging according to the Murphy staging system
Stage I
31
•
A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum
or abdomen
Stage II
•
A single tumor (extranodal) with regional node involvement
•
Two or more nodal areas on the same side of the diaphragm
•
Two single (extranodal) tumors with or without regional node involvement on the same side
of the diaphragm
•
A primary GI tract tumor, usually in the ileocecal area, with or without involvement of
associated mesenteric nodes only
Stage III
•
Two single tumors (extranodal) on opposite sides of the diaphragm
•
Two or more nodal areas above and below the diaphragm
•
All the primary intrathoracic tumors (mediastinal, pleural, thymic)
•
All extensive primary intra-abdominal disease
•
All paraspinal or epidural tumors regardless of other tumors site(s)
Stage IV
•
Any of the above with initial CNS or bone marrow involvement
Diagnosis of BL is made on the presence of medium sized B-cell population, CD10 positive with a
high proliferative rate and multiple genetic lesions: translocation involving MYC gene, point mutations
in regulatory regions associated with MYC and within TP53 tumor suppressor gene. The
pathognomonic criteria for a BL are the translocation t(8;14)(q24;q32) or its alternatives
t(2;8)(p12;q24) t(8;22)(q24;q11) (Bariakh et al., 2005).
Peripheral blood involvement is less common but possible in HIV positive patients, and neoplastic
cells have the characteristics of L3 acute lymphoblastic leukemia (ALL). The population of the cells is
uniform with indistinct nucleoli. A unique morphological variation, AIDS-associated, is plasmacytoid
differentiation. Cells have eccentrically placed nuclei and abundant cytoplasm that contains
immunoglobulins (Grogg et al., 2007).
BL has a very high speed of cell replication and therefore the highest doubling time of any tumor. As a
result BL grows very fast and the tumor can become very large in a short amount of time. To obtain
32
such a high rate of cell proliferation a large number of mitosis and apoptosis takes place, phagocytic
histiocytes containing nuclear debris are seen on low magnitude microscopy as a characteristic ‘starrysky’ appearance (de Leval and Hasserjian, 2009).
It is a therapeutical challenge to treat a HIV positive patient with an intensive chemotherapy; the
immunocompromised state of the patients is thought to be the main difficulty due to the infections
rate. High active antiretroviral therapy (HAART) is administered to HIV positive patients and this
allows treating them with standard chemotherapeutical protocols that are used for HIV negative
patients (Blinder et al., 2008). Other studies (Levine, 2008; Bariakh et al., 2005) suggest that HIV
positive patients will have better results after treatment with a more intensive therapy than HIVnegative individuals.
Due to very high proliferation rates of this type of lymphoma the chemotherapy cycles should be
administered in high doses and with small breaks in between. The capacity of the tumor cells to
develop resistance lowers the effect of less aggressive protocols with lower dose of chemotherapy.
The drugs must have a sufficient half-live to be able to sustain a therapeutical drug concentration in
the blood and it should be not lower than 2-3 days to be able to kill the tumor cells. The consideration
that new protocols will be toxic for HIV positive patients have led to treatment of BL-HIV with the
protocols that are normally given to diffuse large B-cell lymphoma, however this opinion has changed
in recent years. HAART administration has led to a decrease of opportunistic infections (Bariakh et al.,
2005).
33
Figure 3. HIV-positive patient with Burkitt lymphoma. Photo is taken in Hospital №60 (Moscow,
Russia) by Prof. Dr. A.V. Pivnik
Figure 4. HIV-positive patient with Burkitt lymphoma. Photo is taken in Hospital №60 (Moscow,
Russia) by Prof. Dr. A.V. Pivnik
34
4.8. Russian experience of 2002-2005
During three years (2002 –2005) 80 patients with HIV infection were observed. All patients were
examined by a standard scheme with an identification of antibodies to HIV in the ELISA test, viral
load, and broad panel of diagnostic tests for opportunistic infections. Biopsies of the lymph nodes
were made and they underwent a standard processing, sections were stained with haematoxylin – eosin
(Pivnik et al., 2006).
The vast majority of cases were admitted in an expanded stage of AIDS with a minimum of CD4
count (less than 200 cells per µl) and high viral load (hundreds of thousands of copies per µl), with
duration of infection for at least 5 years. Main or a concomitant syndrome was a local or generalized
LA that was revealed in a variety of manifestations of AIDS.
The intravenous use of psychotropic drugs was detected in 94% of the patients, and the remaining
cases occurred due to homosexual and heterosexual transmission. The majority of the patients were
young people from 18 to 30 years, with a predominance of men. The reason for biopsy of peripheral
lymph node was the uncertainty of diagnosis of the disease that determined AIDS and its severity.
Localized enlarged lymph nodes were usually in the neck and supraclavicular areas, rarely in the
axillae. Inguinal lymph nodes were commonly enlarged, dense, up to 2 cm, painless, with unchanged
skin.
Distribution of patients by diagnosis was: tuberculosis diagnosed in 33 patients (41%), lymphoma in
23 (29%) and Hodgkin lymphoma in 5 patients (6%), reactive LA in 15 (19%), germ cell tumors in 3
patients (4%), sarcoidosis in 1 patient (1%). Reactive LA was determined the following histological
picture: follicular hyperplasia - 9 patients, involution - 2 patients, bacterial lymphadenitis with
necrosis - 4 patients. Malignant lymphomas were seen in 29 patients, in 35% of all LA cases (Pivnik et
al., 2006).
In LA three different histological patterns are identified, reflecting an immune response to HIV from
lymphoid hyperplasia through a stage of involution and lymphoid depletion, vascular neoplasia and
sclerosis.
Type A: pattern of acute virus infection
Enlarged lymphoid follicles with hyperplasive germ centers and intensive cytolysis, phagocytosis of
nuclear remnants, histiocytes and numerous mitoses. Small lymphocytes of the mantle zone are
penetrating the follicle. In the surrounding blood vessels and sinuses multiple haemorrhages are seen
along with an accumulation of cells monocytoid nature. Cells are large, uniform, with light cytoplasm
35
and round dark nucleus. Some neutrophils are seen in the sinuses.
Type B: includes properties of type A and C.
The structure of the follicle becomes less clear, partial involution of the germinal centers, lymphoid
depletion, accumulation of plasma cells and proliferation of blood vessels within and around the
follicles. This pattern suggests subacute LA or intermediate phase of progression of HIV infection.
Type C:
Lymph node is atrophic, with small follicles and a distinguished diffuse vascular proliferation.
Follicles are small, almost without lymphocytes, often with a central penetrating arteriole. In a later
stage follicles are indistinguishable, with the focal hyalinosis. In the cortex between the follicles there
is a significantly reduced number of lymphocytes, pronounced vascularization is seen. Often plasma
cells and diffuse fibrosis are seen. The picture looks like a chronic LA with atrophy of the follicles,
significant angiogenesis and fibrosis.
So the LA may be due to an acute stage of HIV infection, which is reflected in the histology of type A,
a progressive decrease in CD4 lymphocytes, characteristic of type B or profound immune depression
in AIDS, which is reflected in the involution of lymphoid follicles and angiomatosis in type C.
LA with HIV infection in the first two stages of the disease (acute and latent) reflects the sequence of
morphological changes in the picture: hyperplasia of lymphoid follicles and their involution and
depletion. Clinical symptoms of LA are local or generalized swelling of painless, elastic, movable
lymph nodes larger than 2 cm. Laboratory findings are reduction of circulating CD4 lymphocytes and
increasing viral load. In the AIDS stage, LA represents a disease it caused: opportunistic infections
and tumors. More rare has the LA a reactive nature, such as follicular hyperplasia in a fresh variety of
viral infections in patients with cured lymphoma. Therefore the biopsy of an enlarged lymph node in
HIV-infected patients in the stage of AIDS allows to make the correct diagnosis of one or more
diseases that define AIDS with a minimal cost (Pivnik et al., 2006).
5. Discussion
As presented in the previous chapters, lymphadenopathy is one of the most profound symptoms of
HIV infection (Gill et al., 2007). Nevertheless, LA is a very broad symptom that can also develop in
individuals that have no HIV infection or immune decline, thus a direct link cannot be made between
LA and HIV. Several particular characteristics such as persistence and generalization of LA have be
to taken into account and a hidden HIV infection must be suspected. It is therefore a challenge to
36
diagnose a HIV infection based only on the anamnesis and clinical examination.
In the following section a description of the list of questions that should be asked in the anamnesis and
items that should be inspected during physical examination is made. These are essential for a diagnosis
of hidden HIV infection based only on the symptom of LA.
•
Anamnesis
Aside from the medical history of a patient attention to the profile of the individual should be given.
This is essential to identify if the individual is a part of a risk group population that has a greater
chance of acquiring the HIV virus. Such groups of people are intravenous drug users, homosexuals,
people that come from or have been in the parts of the world with a significantly higher incidence of
HIV. One of the examples of such a region is Sub-Saharian Africa where two thirds of the people
living with HIV/AIDS worldwide and 76% of the AIDS deaths (The global HIV/AIDS epidemic,
2009) are registered. A special attention has to be given to individuals that practice homosexuality
because of the higher risk of HIV transmission in the ‘men seek men’ group compared with a general
population. Intravenous drug users also have an increased risk of HIV transmission because of the
repetitive use and exchange of contaminated needles. The statistics show that younger people have a
greater chance of HIV infection, so this age can also be used as an important criterion for the risk
profile estimation. In spite of all ‘high risk groups’, the HIV virus can nevertheless be present in
individuals who do not posses any risk factors or do not have a behavior ‘at risk’ (Klimas et al., 2008).
Persistent LA that does not react to the treatment has to raise a suspicion of immune deprivation as a
result of HIV. When a patient with such a symptom undergoes a questionnaire a special attention has
to be given to the number of times, the frequency of the infections and illnesses that took place in
recent time that patient call recall. It is best to compare this number of the infections to the previous
frequency, the number of infections and illnesses that patient had years before. Does the patient feel
that he becomes ill more easily and that there is not always a reason or an explanation for the
infections that he acquires? If patient reports an increase in the frequency, information concerning the
progression and the duration of these infections has to be required. It is alarming when the patient
reports that as a rule it takes longer to recover and that common infections, which also occurred in the
previous time, have a much more severe presentation nowadays.
Information about the appearance and the onset of LA has to be gathered. The speed of the
enlargement of the LNs can be indicative to the discrimination between infected LA and malignant
LA. A fairly quick enlargement that took place in the matter of hours is more suggestive for an
inflectional type of LA. A malignant LA progresses slower and the speed of the onset is moderate.
Due to the fact that some malignant LA, such as for example BL have a very high proliferation rate
37
and therefore a fast growth time, it is very tricky to be able to distinguish the etiology of LA based on
the speed of its appearance (Ferrer, 1998).
The generalization of the LA is also a characteristic to an insufficient immune system and should also
be taken into account and considered as an alarm symptom. Generalized LA is a symptom of the
systemic disease and several LN groups are involved, they are larger than 1 cm and are not matted
(Gill et al., 2007). If such LA is persistent for more than 3 months and the reason for LN involvement
cannot be discovered it is very suggestive for a hidden HIV infection (Gill et al., 2007).
Special attention has to be given to the presence of the secondary symptoms that normally accompany
the persistent generalized lymphadenopathy and can therefore be indications of HIV infection. Night
profound sweats, feeling of malaise, weight-loss, cough, dyspnoea, fever, diarrhea and other signs of
systemic illness can be present with LA. As it was seen in the results these symptoms accompany
different types of LA, infectious and malignant, so it is hard to discriminate the basis for the LN
swelling using these secondary symptoms.
•
Physical examination
A careful investigation of the LA is a very important and essential part of the physical examination of
the patient. It is well known that there is an association of HIV with a several types of tumors resulting
in a significant increase of their prevalence in HIV positive patients. Therefore, a malignant LA can be
encountered and it may be the first clinical symptom of a discrete HIV-infection.
A malignant LA has some specific characteristics that will help to discriminate it from infection-based
LA. A malignant LN has normally a greater size and it is fair to state that there is a direct relationship
between the size and the chance that the enlarged LN is malignant (Ferrer, 1998). BL, for example,
has a high rate of proliferation and frequently results in ‘bulky’ LN (>10cm) (Blum et al., 2004).
Malignant LN are generally not painful unless there is a hemorrhage into necrotic center of the node.
Painful LN are mostly associated with inflammation and are therefore common in infected LN. The
consistency of the LN is more a specific feature that can help in differential diagnosis. Normally
lymphoma presents with LN that have a rubbery consistency, these LN are firm but not hard. The hard
LNs are suggestive for a malignant LN or a cancer metastasis from elsewhere (Ferrer, 1998).
Therefore, stone hard but not painful LA is by all means an alarm symptom. However, when LNs are
matted it can be a symptom of a malignant LA, a lymphoma or metastasic cancer, but are also possible
in benign LNs during an infection with TB or sarcoidosis. The location of the LA is also essential for
the differential diagnosis, for example more than the half of LA in HIV-HL cases are located in the
cervical region. A supraclavicular LA is commonly associated with a malignancy. For a
supraclavicular LA the right or left side of the enlargement is also important due to different drainage
38
of the lymphatic flow in both sides. Swelling of atypical regions, persistent enlargement in irregular
areas such as supracondylar and submandibular regions is common in HIV positive cases (Ferrer,
1998).
The LA that is a result of ongoing opportunistic infections has a slightly different clinical presentation
and the time of onset. In these reactive LNs an inflammation takes place. When inflamed a rapid
enlargement of the LN results in the elongation of the capsule and this makes these enlarged LN
painful while palpated. The speed of the onset is quicker than the speed of growth in malignant LA
(Ferrer, 1998).
Along with an investigation of the LN a thorough examination of the rest of the body has to be made.
The abdominal palpation can result in a complaint of abdominal pain and hepatomegaly and/or
splenomegaly can be encountered. Also symptoms of anemia if present have to be recognized.
If the physical examination directs towards possible malignant LA it is advised to consult a
hematologist to evaluate the patient correctly and to determine the further way of diagnosis and the
treatment.
Fine needle aspiration cytology (FNAC) can be performed and it should either confirm or reject the
primary diagnosis made on the basis of the clinical evaluation. Nevertheless all the precautions have
to be made to minimize the chance for ‘seeding’ and further spread of the possible malignancy. If the
LA is easily accessible an open LN biopsy is one hand a safer procedure and on the other hand it has a
more diagnostic reliability because not only the cells but also the structure of the LN itself can be
examined and evaluated. An estimation of HIV progression is possible by taking a closer look on the
damage and the alteration from the normal structure of the LN.
The group of Gill published results of 6-years study conducted in India that assessed the incidence of
HIV positive individuals, previously undiagnosed for HIV, with LA as a clinical presentation (Gill et
al., 2007). A number of 1082 cases of extra-inguinal LA were analyzed. The screening for HIV was
performed on the blood samples using three different tests. Fine needle aspiration cytology (FNAC)
was performed on palpable and enlarged LN (more than 1 cm in size). Three groups of LNs were
included in the study: cervical, axillary and extra-inguinal. When patients had multiple LNs
enlargement, aspiration from several sites was performed. During this study 25 cases of hidden and
previously undiagnosed HIV infection were discovered. Therefore an incidence of 2.3% of HIV
positives individuals was found in patients presenting with LA. Among the HIV-positives individuals,
15 were male and 10 female, this population was mainly in third and fourth decade and the oldest
patient was 50 years old. None of LA was malignant, 8 cases had reactive lymphadenitis, 15 had TB
39
and 2 non-TB granulomatous lymphadenitis (Gill et al., 2007). This means that LA is a symptom that
on its own should make doctors alert for a possible HIV infection. The study of Gill reports that no
similar studies were conducted to compare and verify or neglect this incidence of HIV positiveness in
LA patients. Our literature study confirms this since no recent publications with similar investigation
were found.
During my literature study it became apparent that a very low, limited amount of the information in
the scientific literature is devoted to describe the features, characteristics and clinical presentation of
the LA. A very restricted explanation was present describing the particular symptoms of the LN
enlargement. No publication have been found with a detailed report about the features of the LA that
could help a doctor to examine the LA properly and to identify crucial features of LA. Most of the
authors gave only a brief description stating the presence of LA but no details were given. As a rule
much more emphasis was devoted to the pathogenesis and histology of the particular disease. This
lack of useful information that can be used in clinical practice raised a question why so little attention
is given to a very broad symptom. No practical information is given for the general practitioners that
lack the specific experience and knowledge and would only thrive from more detailed information
about the various LA characteristics.
It was also difficult to find information describing the clinical characteristics of the enlarged or normal
LNs. All the handbooks and manuals gave a more specific data about the inner structure of the node
but no details or description about the types of clinical presentations.
On the whole not enough data is supplied to distinguish between the LA of different etiologies and
therefore, usage of specific tests plays a crucial role in the differential diagnosis. It seems that the
clinical characteristics of the LN such as consistency, size or matting are not sensitive and/or specific
enough to mention them in the articles or reviews. Maybe authors feel that this information is already
well known to the doctors and is not worth repeating.
In the summer of 2009 a 6-week visit was made to 2 medical institutions in Moscow, Russia. The first
hospital was the Hematological Scientific Center (HSC) that is a clinic that specializes only in
treatment of patients with hematological disease. A number of patients with diffuse B-large cell
lymphoma, HL and BL were observed however none of them were HIV positive. Nevertheless a close
look on the method of treatment, the protocols and the progression of the diseases was made.
A modification of the BL protocol is invented and applied in HSC, a LB-M-04 protocol. It is a
modification of the Hoeltzer-protocol that is commonly used (NHL-BFM-90). The reason for the
change, the intensification of the protocol is to have an effect on the tumor before the forming of
40
resistance of the tumor cells to chemotherapy. The Hoeltzer-protocol consists of 6 cycles of
chemotherapy; three different types (type A, type B and type C) are administered one after another.
Table 3. Types of chemotherapy in the protocol NHL-BFM-90
Type A
Type B
Type C
Dexamethasone 20 mg, day 1-5
Doxorubicin 25 mg/m², day 3
Vincristine 2 mg, day 1
Vincristine 2 mg, day 1
Ifosfamide 800 mg/m², day 1-5
Methotrexate 1500 mg/m², day 1
Methotrexate 1500 mg/m², day 1
Dexamethasone 20 mg, day 1-5
Cytarabine 150 mg/m², day 4-5
Cyclophosphamide 200 mg/m², day 1-5
Dexamethasone 20 mg, day 1-5
Etoposide 150 mg/m², day 3-5
Vinblastine 10 mg, day 1
Cytarabine 2 g/m² 2 times per day, day
2-3
Etoposide 100 mg/m², day 4-5
In the modification of the protocol only 4 cycles are applied, but LB-M-04 protocol is intensified and
the duration of the therapy is reduced. The types of the chemotherapy are altered and the combination
of the drugs is changed. The interval between the cycles is 21 day and treatment takes around 3
months. They report that as a result of high chemotherapeutical sensitivity BL is completely regressing
after two cycles of the therapy even when the tumor mass is considerably big, so the effect of the
therapy does not depend on the size of the tumor. To reduce the agranulocytosis duration colonystimulating factor (CSF) is used (Bariakh et al.,2005).
41
Table 4. Types of chemotherapy in the protocol LB-M-04
Type A
Type C
Dexamethasone 20 mg, day 1-5
Dexamethasone 20 mg, day 1-5
Vincristine 2 mg, day 1
Etoposide 150 mg/m², day 3-5
Ifosfamide 800 mg/m², day 1-5
Methotrexate 1500 mg/m², day 1
Methotrexate 1500 mg/m², day 1
Vinblastine 10 mg, day 1
Cytarabine 150 mg/m², day 4-5
Cytarabine 2 g/m² 2 times per day, day 2-3
Etoposide 100 mg/m², day 4-5
Lumbar punction with an intrathecal injection of Cytarabine
30mg, Methotrexate 15mg, and Dexamethasone 4mg on the 1
day
Doxorubicin 25 mg/m², day 3
Lumbar punction with an intrathecal injection of Cytarabine
30mg, Methotrexate 15mg, and Dexamethasone 4mg on the 1
day
17 (85%) of the patients got a remission after a LB-M-04 protocol. One early relapse was diagnosed
and three patients died of complications of chemotherapy. The average length of the treatment was 33.5 months. 3-year survival is registered at 80%. After each cycle of the therapy a status of a
myelotoxic agranulocytosis was reached (less than 100 neutrophils cells per µl). The median duration
was 6.3 days with variation between 1 and 23 days. In 87% of the cycles a type of infectious
complication was recorded. Fever was seen in 65% of the cases, stomatitis in 42%, necrotic
enteropathy in 14%, mucositis in 6%, sepsis in 8%, pneumonia in 8%, proctitis and paraproctitis in 5%
and a fever without an infection in 16%. The most amounts of complications were seen in the first
cycle A that can be explained by a severe state of the patients at the moment of hospitalization.
(Bariakh et al., 2005)
Another hospital that was visited in Moscow was the hospital №60. A part of the hematological
department is devoted to the treatment of HIV associated lymphomas. Newly developed protocol LBM-04 for the treatment of BL is already applied there. Due to the fact that this modified protocol is
associated with and an intensification of the treatment more attention to the conditions of the patients
along with the ‘reverse isolation’ of patient is crucial to prevent opportunistic infections and possible
complications. It is sad to report that none of these conditions are provided. Patients with severe
immunosuppression and myelotoxic agranulocytosis are placed in the same small rooms, sharing the
infections with the neighbor. No isolation possibilities are available. A lack of funding for better
conditions, which are an absolute necessity for the treatment of HIV- associated lymphoma with high
dose chemotherapy, was apparent.
42
Before the beginning of the therapy of the lymphoma it is vital to have a correct diagnosis. When a
lymphoma is misdiagnosed, for example a BL that was wrongly thought to be a HL and treated
according to the HL protocol will afterwards react very poorly to the correct, appropriate treatment
and become refractory. The tumor forms resistance for particular chemotherapeutical drugs and it
reduces the chances of a successful treatment significantly. Several examples of such refractory
patients that are noncompliant to the chemotherapy were observed in HSC. Therefore the lymphomas
that are diagnosed in HIV positive patients should be diagnosed and evaluated correctly by a multi
disciplinary team that consists of several types of doctors one of which should be an experienced
hematologist. HIV associated malignancies are combinations of severe diseases and the reaction and
assessment of the medical team has to be appropriate.
Vigilance and high degree of suspicion for a hidden HIV infection is essential when patients with LA
are encountered.
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