Bronchopneumonia tends to be patchy, although, if severe, even bronchopneumonia may become confluent and involve an entire lobe of lung.
Streptococcus pneumoniae.
This patient appears to be a chronic alcoholic who is probably malnourished and somewhat immunosuppressed. Alcoholics are also prone to aspirate bacteria laden secretions from the upper respiratory tract during an alcoholic bout. In all likelihood, impaired mucociliary clearance and defective phagocytic functions of alveolar macrophages also contributed to lung infections.
Bacteria typically cause acute inflammation, characterized by congestion, formation of an exudate, and a polymorphonuclear infiltrate.
The most common complications of viral pneumonitis are secondary bacterial pneumonia and diffuse alveolar damage.
The sputum is comprised of the exudate in the alveoli; it is rusty because of the red cells in the exudate.
Staphylococcus aureus, Klebsiella pneumoniae, and type 3 pneumococcus.
Abscess formation, empyema, organization with subsequent fibrosis, bacteremic dissemination.
Primary pulmonary tuberculosis is usually asymptomatic, the residua of which is the Ghon complex. Secondary, or reactivation, tuberculosis typically occurs years after the primary infection and most commonly involves the apex of the lungs. Here it typically causes caseation necrosis and cavitation. With healing there is fibrosis. Either of these types of tuberculosis may become progressive, that is, evolve into miliary tuberculosis or tuberculous bronchopneumonia.
The collagen fibers suggest that the process has been a chronic one, with organization of the inflammatory response to the organism.
Immunosuppressed patients are more likely to have disseminated infection, involving lymph nodes, blood, central nervous system, and bowel. The host reaction is less likely to have well-formed granulomas and more likely to consist of histiocytes and necrosis. Acid fast organisms are abundant.
Miliary tuberculosis refers to blood-borne spread of tuberculosis. It more commonly occurs in patients who are immunosuppressed, particularly patients undergoing cancer chemotherapy or dialysis, in transplant recipients, or in HIV-infected persons. In developing countries, children are also particularly susceptible.
Patients with fungal pneumonia may have pulmonary damage from vascular occlusion by the fungus, resulting in ischemic necrosis, or from direct invasion and host reaction to the organism.
Paranasal sinuses, with extension to the brain (rhinocerebral mucor).
Neutrophils are more commonly present in bacterial infection than in viral infection. Most viruses that cause diarrhea affect the small intestine and do not cause ulceration or invade the mucosa. Cytomegalovirus is one virus that does not follow this rule, as it causes ulceration secondary to ischemic necrosis and direct invasion. However, this is not a common cause of infectious diarrhea in the immunocompetent host.
The major factors that contribute to the pathogenesis of Clostridium difficile induced pseudomembranous colitis are:
a. Alteration of the normal intestinal bacterial flora.
b. Toxin production by rapidly growing Clostridium difficile at a time when the growth of the other normal competing intestinal organisms are suppressed. C. difficile produces two toxins: toxin A is an enterotoxin, and toxin B is a cytotoxin. The toxins cause direct damage to the epithelium and also result in localized vascular thrombosis, which further causes epithelial destruction.
c. Age-related susceptibility. Neonates and infants up to one year of age commonly harbor Clostridium difficile in their normal intestinal flora without deleterious effects. Population-based studies have shown an increased incidence of Clostridium difficile toxin-positive stools 20- to 100-fold in the 60+ year old age group as compared to the 10-20 year old age group. In this patient, the normal flora of the gastrointestinal tract was altered by antibiotic therapy, which allowed for overgrowth of Clostridium difficile.
In addition to C. difficile, other organisms that cause such lesions are Staphylococci, shigella, candida, CMV.
The toxins produced by C. difficile cause epithelial damage, which results in sloughing of the epithelium. In addition there is an intense inflammatory response and formation of an exudate. The necrotic epithelium and the inflammatory exudate together form the pseudomembrane.
The colon in patients with cholera is edematous, without any other pathologic changes. Cholera is also a toxin-mediated disease, but epithelial destruction does not occur.
The material forming the pseudomembrane consists of fibrin, neutrophils, and cellular debris, which is different from a membrane, composed of epithelial cells.
Viral enteritis is a disease of the small intestine, and bacterial colitis is usually a disease of the colon. Bacterial enterocolitis incites a neutrophilic response, in contrast to viral enteritis, which typically induces a mononuclear response.
Acute bacterial gastroenteritis is most commonly associated with campylobacter, shigella, salmonella, or toxigenic E. coli.
Giardia typically is associated with mild villous blunting in the small intestine and a mixed infiltrate in the lamina propria, although the morphologic changes may vary from none to severe villous blunting.
The cysts are the infectious form of the organism. These are swallowed, with release of the trophozoites.
The liver is the typical location for amebic abscesses. Rarely, the amebae may disseminate to the lungs and brain.
The laboratory tests used to aid in the diagnosis of diarrhea include stool for leukocytes (negative in viral infections; positive in bacterial infection, particularly when invasive). Stool culture may be done to detect Salmonella spp., Shigella spp., Campylobacter spp., V. cholerae, and pathogenic E. coli routinely. If Yersinia spp. is a consideration, this may be cultured but requires special techniques. C. difficile is not routinely cultured from stool. It is an anaerobe that requires special media, and most labs do not routinely attempt to culture the organism. Stool for ova and parasites will detect Amoeba and Giardia. Serologic tests for amoeba and direct antigen testing for giardia and cryptosporidium are also useful. In addition, rotavirus antigen may be detected by EIA. The gold standard for Clostridium difficile detection is the cytotoxicity assay.
In general, the serologic diagnosis of syphilis should consist of a non-treponemal test (VDRL or RPR) followed by confirmation with a treponemal-specific test (MHA-TP or FTA-Abs). Because of the high false negative rate of the non-treponemal tests in tertiary syphilis, if the screening non-treponemal test is negative, a specific treponemal test should be ordered to help confirm the diagnosis. See Table below:
|
|
||||
|
Stage |
RPR |
VDRL |
MHA-TP |
FTA-Ab |
|
Primary |
86 |
80 |
82 |
98 |
|
Secondary |
100 |
100 |
100 |
100 |
|
Tertiary |
73 |
71 |
94 |
96 |
The chancre is present in primary syphilis.
Silver stains, not routine bacterial stains, are necessary to see the organisms in tissue sections. These are typically either the Steiner stain or the Warthin-Starry.
Either the RPR or the VDRL, followed by either the MHA-TP or the FTA-Abs
No.
Herpes simplex virus typically infects the liver, lungs, adrenals, and central nervous system.
Perinatal HSV infection, either type I or type II, is usually acquired at the time of delivery through an infected birth canal; therefore, this is considered ascending rather than transplacental, which would mean hematogenous dissemination from the mother to the infant. This is in contrast to most other perinatal viral infections, which are acquired from a hematogenous dissemination from the mother. The clinical course of neonatal HSV infection is dependent upon whether the maternal infection is primary or recurrent. If the maternal infection is recurrent, protective antibody passes to the fetus through the placenta, and only 3% of the infants contract the virus. Most of these infants are mildly affected, but disseminated infection may occur in this group, particularly in the face of prematurity. In pregnancies in which a primary infection occurs in the mother, there is a 50% risk for neonatal infection if the infant is delivered through an infected birth canal because of a lack of protective antibodies. In this case, the presumed primary infection in the mother was silent, which is the scenario in 70% of cases of congenital HSV infection. The infants usually become symptomatic 5-8 days after delivery.
Bones of the nose and lower legs are most commonly affected by the osteochondritis and periostitis.
The maternal and neonatal picture is more consistent with HSV than with syphilis. The maternal RPR showed a four-fold decrease from her titer at diagnosis, indicating that the penicillin treatment was effective. Syphilis does not produce vesicles; these are more characteristic of HSV. Additionally, the smear of the lesions, seen in Image 5, is characteristic of HSV. Syphilis characteristically presents in the neonate with a rash and osteochondritis. The pathology is quite different in that syphilis shows fibrosis, endarteritis, and plasmacytic infiltrates.
Fibrosis most commonly occurs in the liver, pancreas, and lungs, but may be present in multiple organs. The typical morphology of congenital syphilis in the brain is that of a chronic meningitis.
Cytomegalovirus produces an ependymitis, so the calcifications are typically periventricular.
Congenital parvovirus infection is acquired by the fetus in utero secondary to transplacental passage of virus from mother to fetus. This occurs at the time of maternal viremia.
The aplastic crisis of sickle cell anemia is caused by parvovirus B19. Patients with other hemoglobin disorders, such as hemoglobin SC disease, thalassemia, and hereditary spherocytosis, may develop aplastic crises with parvovirus B19 infection as well.
The bacterial organisms causing meningitis may be divided as follows:
Neonates: group B streptococcus, E. coli, listeria
Infants and children: S. pneumoniae and N. meningitidis
Adults: S. pneumoniae and gram negative rods
The clinical diagnosis is bacterial meningitis secondary to S. pneumoniae. This bacterium is a gram positive lancet-shaped coccus, often occurring in pairs. The patient had an upper respiratory tract infection associated with otitis media, predisposing her to the development of meningitis.
The inflammation reaches the CNS through the meningeal vasculature; therefore, one would expect concentration of white blood cells at this location.
|
Disorder |
|
|
|
|
|
Normal |
|
|
|
|
|
Bacterial Meningitis |
|
|
|
|
|
Aseptic Meningitis |
|
(netrophilic early) |
|
|
|
Tuberculous Meningitis |
|
(+/-neutrophilic) |
|
|
|
Viral Meningoencephalitis |
|
|
|
|
|
Brain Abscess |
|
(+/-neutrophilic) |
|
|
|
Cryptococcal Meningitis |
|
|
|
|
In a significant proportion of patients with bacterial meningitis (less than 50%), the CSF glucose is normal at the time of diagnosis. In this case, the glucose was normal, but it decreased because of the progression of the disease. The organism was not sensitive to the first antibiotic used; therefore, the glucose decreased as expected with bacterial meningitis.
Arachnoid fibrosis occurs secondary to meningeal scarring from the inflammatory response to the bacteria in the meninges.
This is a chronic process because of the degree of fibrosis.
Cerebral necrosis may occur as a result of direct extension of the organism into the brain or due to vasculitis with secondary ischemic necrosis.
Viral meningitis does not have an associated vasculitis, nor does it cause this degree of meningeal inflammation.
A tuberculoma that would show characteristic granulomas with Langhans' giant cells.
Macroscopically, viral meningitis shows only cerebral edema.
Alterations in mood, memory, and behavior are the most common presenting symptoms.
One may see viral inclusions in both HSV I and HSV II encephalitis. These inclusions may be found in both neurons and glia.
The main routes of bacterial transmission to the CNS that result in abscess formation include hematogenous dissemination, direct implantation from trauma, and local extension as from the sinuses.
Focal neurologic deficits.
Cryptococcus is inhaled and causes initially a pulmonary infection that undergoes hematogenous dissemination to the central nervous system.
Cryptococcal meningitis occurs in the setting of immunosuppression. It is particularly common in those with AIDS.
The lungs appear atelectatic, red, and firm.
Bronchial washings or sputum samples may be collected to diagnose pneumocystis.
The course is typical. There are three phases of HIV infection. The first (early, acute) phase is characterized by a high level of virus production and viremia; the symptoms are non-specific. In the second (middle, chronic) phase, which was the initial presentation here, there is a smoldering, low-level HIV replication, predominantly in lymphoid tissues, which may last several years. The final (crisis) phase is characterized by a breakdown of host defenses, viral replication, and the symptoms of persistent fever, fatigue, weight loss, and diarrhea.
HIV infection is stratified into three categories: CD4+ cells greater than or equal to 500/µL; 200-499/µL; <200/µL. If the count is above 500/µL, there is a low probability of progression. If the count is below 200/µL, or is rapidly falling, the probability of progression is high.
In this patient, the testing used was the ELISA, Western Blot, and CD4+ counts. The ELISA HIV-1 antibody test is the first line test to assess whether the patient has an HIV infection. Presumably, the test was positive in this case, which prompted the confirmatory Western Blot. The HIV-1 ELISA has excellent sensitivity and specificity (>99%); however, due to the gravity of the diagnosis, a confirmatory test is done. The Western Blot confirms the presence of the HIV antibody. In this test, HIV antigens are electrophoresed on a gel, transferred to a membrane, and overlaid with the patient's serum. The classic pattern of HIV positivity shows 9 bands. The HIV p24 antigen test also uses ELISA methodology to look for the viral particles in the serum before antibodies rise. This test is currently used, along with the HIV-1 antibody test, to screen blood units donated in the United States. The polymerase chain reaction amplification for HIV-1 is now the method of choice for assessing viral load and response to therapy in patients with AIDS, and it is supplanting the p24 antigen test in these situations. The PCR is also used to diagnose perinatally-acquired HIV infection because the HIV-1 antibody test in the perinatal period reflects the mother's status instead of the infant's; therefore, the antibody test has limited value until about 15 months of age.
Approximately 30-50% of patients with AIDS have neurologic impairment during the course of their illness.
Many processes need to be considered in the differential diagnosis of altered mental status in this patient. In general, one needs to think about two general categories here: opportunistic diseases and primary HIV-associated syndromes. The opportunistic processes include viral infection (CMV and progressive multifocal leukoencephalopathy), bacterial infections (tuberculosis and pyogenic bacterial infections), fungal infections (especially cryptococcosis, but also histoplasmosis and coccidioidomycosis), and parasitic infections (toxoplasmosis). Primary and metastatic CNS lymphomas are the only important opportunistic neoplasms; Kaposi's sarcoma is almost unheard of in the CNS. The absence of focal lesions by CT scan suggests that this is not toxoplasmosis, CNS lymphoma, or an abscess. The absence of focal white matter lesions in the MRI excludes progressive multifocal leukoencephalopathy. Another important, treatable cause of altered mental status, cryptococcosis, can be excluded (for practical purposes) by negative CSF cryptococcal antigen test. The generalized cerebral atrophy is quite consistent with cytomegalovirus encephalitis and primary HIV encephalopathy, both of which were present at autopsy. Primary HIV encephalitis is the most common CNS disease in patients with AIDS. HIV encephalitis produces a progressive decline in cognitive function, manifested first by memory loss and withdrawal. It typically affects deep gray matter and white matter, and in the present case is responsible for the white matter pallor apparent at autopsy.
Progressive multifocal leukoencephalopathy is another disease that may result in demyelination in this patient population.
HIV-1 aseptic meningitis, although not well studied, typically shows a mild lymphocytic meningitis with some myelin loss. HIV-1 meningoencephalitis is typified by a parenchymal inflammatory reaction that occurs in a scattered and perivascular pattern. In addition, there are microglial nodules that contain giant cells derived from macrophages.
Most often CMV may be found in the salivary glands, kidneys, liver, lungs, gut, pancreas, thyroid, adrenals, and brain (to name a few!).
The common pathogens producing diarrhea in patients with AIDS include mycobacterium avium-intracellulare, cryptosporidiosis or isosporidiosis, and cytomegalovirus. In addition, a general rule is that any pathogen that infects the immunocompetent patient may also infect the immunocompromised patient, which would leave all the common bacterial and viral pathogens on this list as well.
Cryptosporidiosis is not invasive. The organisms attach to the superficial portions of the intestinal epithelium. By comparison, MAI organisms are found in histiocytes in the lamina propria and submucosa.
In immunocompetent patients, an acute CMV infection results in a syndrome resembling acute infectious mononucleosis. In the immunosuppressed patient, CMV disease, whether acquired primarily or a result of reactivation may be a disseminated, fulminant, and lethal disease with multiorgan involvement.
Both CMV and C. difficile may produce colitis with pseudomembranes. In CMV disease, the pseudomembranes result from direct epithelial necrosis and, probably more importantly, ischemic necrosis secondary to vascular damage by CMV. In C. difficile-associated pseudomembranous colitis, the pseudomembranes result from toxin-mediated destruction of the epithelium as well as vascular thrombosis of underlying small vessels.
PML is a disease of immunosuppressed patients, those who have AIDS or leukemias/lymphomas, and those on immunosuppressive therapy. Its incidence in AIDS ranges from 1 to 6%.
Toxoplasma causes pneumonitis, lymphadenitis, and chorioretinitis, as well as encephalitis.
The CSF would show malignant lymphoid cells.
Patients with Kaposi's sarcoma may have life-threatening hemorrhage from intestinal involvement by Kaposi's sarcoma.