Oppurtunistic infections in AIDS
- 1. Opportunistic infections in AIDS Aseem Jain Resident of Pathology
- 2. • HIV infection/AIDS is a global pandemic, with cases reported from virtually every country. • According to UNAIDS Gap report 2016 India has the third largest HIV epidemic in the world. • There are 2.1 million people living with HIV in India which constitutes 0.3% of adult HIV prevalence. • 86000 new cases were diagnosed in past year and 68000 people died of AIDS in 2015.
- 3. • Retrovirus • Retroviridae family • 7 subfamilies • HTLV & HIV • 70-130nm • Lipid envelope • Icosahedral capsid • Core • RNA • Enzymes
- 6. Transmission
- 7. Clinical features • HIV disease begins with acute infection, which is only partly controlled by adaptive immune responses and advances to chronic progressive infection of peripheral lymphoid tissues. • Virus typically enters through mucosal epithelia. • The pathogenetic events and clinical manifestations of the disease can be divided into several phases – 1. Acute retroviral syndrome 2. Middle, chronic phase 3. Clinical AIDS
- 10. Category A • Consists of one or more of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection. • Conditions listed in categories B and C must not have occurred. • Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection.
- 11. Category B • Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C and that meet at least one of the following criteria: 1. The conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or 2. The conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection.
- 12. 1. Bacillary angiomatosis 2. Candidiasis, oropharyngeal (thrush) 3. Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy 4. Cervical dysplasia (moderate or severe)/cervical carcinoma in situ 5. Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month 6. Hairy leukoplakia, oral 7. Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome 8. Idiopathic thrombocytopenic purpura 9. Listeriosis 10. Pelvic inflammatory disease, particularly if complicated by tuboovarian abscess Peripheral neuropathy
- 13. Category C • Conditions listed in the AIDS surveillance case definition. 1. Candidiasis of bronchi, trachea, or lungs 2. Candidiasis, esophageal 3. Cervical cancer, invasivea 4. Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary 5. Cryptosporidiosis, chronic intestinal (>1 month's duration) 6. Cytomegalovirus disease (other than liver, spleen, or nodes) 7. Cytomegalovirus retinitis (with loss of vision)
- 14. 8. Encephalopathy, HIV-related 9. Herpes simplex: chronic ulcer(s) (>1 month's duration); or bronchitis, pneumonia, or esophagitis 10. Histoplasmosis, disseminated or extrapulmonary 11. Isosporiasis, chronic intestinal (>1 month's duration) 12. Kaposi's sarcoma 13. Lymphoma, Burkitt's (or equivalent term) 14. Lymphoma, primary, of brain 15. Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary 16. Mycobacterium tuberculosis, any site (pulmonarya or extrapulmonary) 17. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
- 15. 18. Pneumocystis jiroveci pneumonia 19. Pneumonia, recurrent 20. Progressive multifocal leukoencephalopathy 21. Salmonella septicemia, recurrent 22. Toxoplasmosis of brain 23. Wasting syndrome due to HIV
- 16. Primary HIV infection, Viral dissemination & Acute retroviral syndrome
- 19. Chronic phase • Despite the robust cellular and humoral immune responses that are mounted following primary infection, once infection has been established the virus succeeds in escaping immune-mediated clearance, paradoxically seems to thrive on immune activation, and is never eliminated completely from the body. • Rather, a chronic infection develops that persists with varying degrees of continual virus replication in the untreated patient for a median of ~10 years before the patient becomes clinically ill.
- 20. • It is this establishment of a chronic, persistent infection that is the hallmark of HIV disease. • In chronic phase of the disease, Lymph nodes and spleen are the sites of viral replication and cell destruction. • Destruction of CD4+T cells within the lymphoid tissues continues during this phase & number of circulating CD4+T cells steadily declines. • Eventually over a period of years, the continuous cycle of virus infection, T cell death, and new infection leads to a steady decline in number of CD4+T cells in lymphoid tissues and circulation.
- 21. • Concomitant with this loss of CD4+T cells, hosts defenses begin to wane. • HIV RNA levels begin to rise as the host loses his battle against the virus. • Patients are either asymptomatic or develop minor opportunistic infections in this phase. • Opportunistic infections include oral candidiasis, vaginal candidiasis, herpes zoster and perhaps mycobacterial tuberculosis.
- 22. Evasion of immune system control • Inherent to the establishment of chronicity of HIV infection is the ability of the virus to evade elimination and control by the immune system. • There are a number of mechanisms whereby the virus accomplishes this evasion – 1. establishment of a sustained level of replication associated with the generation of viral diversity via mutation and recombination, thus providing a means to evade control and elimination by the immune system. 2. Downregulation of HLA class I molecules on the surface of HIV-infected cells 3. Mechanisms to evade neutralizing antibodies
- 23. •Latent infected CD4+T cells act as Reservoir of HIV. •Post integration latency (Stable). •Pre integration latency (Unstable)
- 24. Clinical AIDS/Advanced HIV disease • In untreated patients or in patients in whom therapy has not adequately controlled virus replication, after a variable period, usually measured in years, the CD4+ T cell count falls below a critical level (<200/L) and the patient becomes highly susceptible to opportunistic disease. • Patients may experience constitutional signs and symptoms or may develop an opportunistic disease abruptly without any prior symptoms. • The depletion of CD4+ T cells continues to be progressive and unrelenting in this phase.
- 25. • It is not uncommon for CD4+ T cell counts in the untreated patient to drop as low as 10/L or even to zero. • In the absence of treatment, most but not all patients with HIV infection progress to AIDS after a chronic phase lasting from 7-10 years. • Rapid progressors – Chronic phase of 2-3 years. • Long term non progressors – asymptomatic for 10 years or more with stable CD4+T cells counts. • Elite controllers – Infected but undetectable plasma viremia (50-75 RNA/ml)
- 26. Lab diagnosis of HIV 1. Enzyme immunoassay (EIA) – Screening test 2. Western blot - Confirmatory 3. p24 antigen capture assay 4. Nucleic acid testing/HIV RNA determination 5. CD4+T cell counts • EIA + Western blot = Confirmatory.
- 28. •Patients with CD4+ T cell counts <200/μL are at high risk of disease from P. jiroveci, while patients with CD4+ T cell counts <50/μL are at high risk of disease from CMV, mycobacteria of the M. avium complex (MAC), and/or T. gondii
- 29. 1) Screening (E/R/S) tests a. ELISA b. Rapid tests - Dot blot assay - Particle agglutination (Latex,Gelatin) - HIV spot and comb tests c. Simple tests - These are based on ELISA principle 2) Supplemental tests - Western blot tests - Indirect immunofluorescence test - Radio immuno precipitation assay
- 30. Opportunistic Infections Protozoal and helminthic infections 1. Cryptosporidiosis (enteritis) 2. Toxoplasmosis (pneumonia or CNS infection) Fungal Infections 1. Candidiasis 2. Cryptococcosis 3. Coccoidiomycosis 4. Histoplasmosis 5. Pneumocystosis Bacterial infections 1. Mycobacteriosis 2. Nocardiosis 3. Salmonella infections Viral infections 1. Cytomegalovirus 2. Herpes simplex virus 3. Varicella zoster virus 4. Progressive multifocal leukoencephalopathy
- 31. Cryptosporidiosis • Result of infestation by a coccidial protozoan, Cryptosporidium. • In sections, the organisms appear as 2–5 µm basophilic spherical structures attached to the luminal surface of the epithelium. • The organisms stain well with Giemsa, silver methenamine, and PAS, but are not acid-fast .
- 32. • Cryptosporidia, microsporidia, and Isospora belli are the most common opportunistic protozoa that infect the gastrointestinal tract and cause diarrhea in HIV-infected patients. • Cryptosporidial infection may present in a variety of ways. • In 75% of cases the diarrhea is accompanied by crampy abdominal pain, and 25% of patients have nausea and/or vomiting. • Cryptosporidia may also cause biliary tract disease in the HIV-infected patient, leading to cholecystitis with or without accompanying cholangitis. • The diagnosis of cryptosporidial diarrhea is made by stool examination.
- 34. Toxoplasmosis • Toxoplasmosis is the generic designation applied to localized or systemic infections caused by the obligate intracellular protozoan Toxoplasma gondii. • Leading cause of space-occupying intracranial lesions in the HIV-1 seropositive. • Toxoplasma ‘abscesses’ favor neuron-rich gray matter structures such as the cerebral cortex, basal ganglia, and brainstem. • seizures, progressive hemipareses, and cranial nerve deficits figure prominently among their initial manifestations.
- 36. Pneumocystosis • Pneumocystis carinii (recently renamed Pneumocystis jirovecii) pneumonia is a nonbacterial opportunistic infection. • In severely immunocompromised patients, the infection may spread to extra pulmonary sites and become disseminated. • The risk of PCP is greatest among those who have experienced a previous bout of PCP and those who have CD4+ T cell counts of <200/L. • Overall, 79% of patients with PCP have CD4+ T cell counts <100/L and 95% of patients have CD4+ T cell counts <200/L.
- 37. • Patients with PCP generally present with fever and a cough that is usually nonproductive or productive of only scant amounts of white sputum. • They may complain of a characteristic retrosternal chest pain that is worse on inspiration and is described as sharp or burning. • Otic involvement may be seen as a primary infection, presenting as a polypoid mass involving the external auditory canal. • Other organs that have been involved include lymph nodes, spleen, liver, kidney, pancreas, pericardium, heart, thyroid, and adrenals.
- 39. Candidiasis • Thrush, due to Candida infection, is usually indicative of fairly advanced immunologic decline; it generally occurs in patients with CD4+ T cell counts of <300/L. • Thrush appears as a white, cheesy exudate, often on an erythematous mucosa in the posterior oropharynx. • While most commonly seen on the soft palate, early lesions are often found along the gingival border. • The diagnosis is made by direct examination of a scraping for pseudohyphal elements. • Culturing is of no diagnostic value.
- 40. • Candida esophagitis can complicate the ulcers of herpes or CMV esophagitis or appear in the absence of viral infection. • It may also be seen secondarily to esophageal stricture or in children as mucocutaneous candidiasis, an expression of an immunologic deficiency. • The diagnosis can be made by brush cytology.
- 41. Cryptococcosis • Cryptococcus neoformans frequently presents as an opportunistic infection in patients with AIDS. • Patients with pulmonary cryptococcal disease present with fever, cough, dyspnoea, and in some cases, hemoptysis.
- 42. • Organisms may evoke virtually no inflammatory reaction, so gelatinous masses grow in the meninges or expand the perivascular Virchow-Robin spaces within the gray matter producing the so called ‘Soap bubble lesions’.
- 43. Mycobacteriosis • Worldwide, approximately one-third of all AIDS-related deaths are associated with TB. • HIV infection increases the risk of developing active TB by a factor of 100. • In one study, the median CD4+ T cell count at presentation of TB was 326/L. • The clinical manifestations of TB in HIV-infected patients are quite varied and generally show different patterns as a function of the CD4+ T cell count. • Approximately 60–80% of patients have pulmonary disease, and 30–40% have extra pulmonary disease.
- 44. • Atypical mycobacterial infections are also seen with an increased frequency in patients with HIV infection. • The most common atypical mycobacterial infection is with M. avium or M. intracellulare species—MAC. • It has been suggested that prior infection with M. tuberculosis decreases the risk of MAC infection. • MAC infection is a late complication of HIV infection, predominantly occurring in patients with CD4+ T cell counts of <50/L (average 10/L). • The most common presentation is disseminated disease with fever, weight loss, and night sweats. • The diagnosis is made by the culture of blood or involved tissue.
- 46. • Infections with enteric pathogens such as Salmonella, Shigella, and Campylobacter are more common in homosexual men and are often more severe and more apt to relapse in patients with HIV infection. • Patients with untreated HIV have approximately a 20-fold increased risk of infection with S. typhimurium. • They may present with a variety of nonspecific symptoms including fever, anorexia, fatigue, and malaise of several weeks' duration.
- 47. Cytomegalovirus • CMV is an important pathogen in patients with advanced HIV infection in whom it often causes retinitis or disseminated disease, particularly when peripheral-blood CD4+ T cell counts fall below 50–100/L.. • This can be either primary infection or reactivation of latent CMV. • CMV is the most common opportunistic viral pathogen in AIDS.. • CMV infection primarily affects the lungs (pneumonitis) and GIT (colitis). • It also affects CNS (encephalitis) and Eye (retinitis).
- 48. • The development of tachypnea, hypoxia, and unproductive cough signals respiratory involvement. • Gastrointestinal CMV involvement may be localized or extensive and almost exclusively affects compromised hosts. • Two forms of CMV encephalitis are seen in patients with AIDS (HIV encephalitis / Ventriculoencephalitis). • CMV retinitis is an important cause of blindness in immunocompromised patients
- 50. Varicella zoster virus • Two conditions – Chicken pox and Shingles. • Acute infection with VZV causes chicken pox while reactivation of latent VZV causes shingles. • Shingles is a cause of morbidity in elderly and immunocompromised people. • VZV evades immune responses and establishes a latent infection in sensory ganglia. • VZV infects neurons and/or satellite cells around neurons in the dorsal root ganglia and may recur many years after primary infection. • Recurrence generally does not occur but may occur in HIV infected individuals
- 53. References 1. Robbins and Cotran Pathologic basis of disease 8th edition 2. Harrison’s principles of internal medicine 19th edition 3. Rosai and Ackerman's Surgical Pathology 10th edition
- 54. Thank you