Pulmonary Manifestations of CMV and Influenza in HIV Patients

1. Viral And Parasitic Pulmonary Manifestations In HIV And Pulmonary Neoplasia In HIV DR. KOMALDEEP JR PULMONARY MED TBHP

3. CYTOMEGALOVIRUS – CMV • Complex DNA virus - B- group of the family Herpesviridae. • It is the largest virus that infects the humans. • Production of characteristics enlarged cells. • Establishes latency - polymorphonuclear cells, T lymphocytes & salivary glands • Once infected, an individual probably carries CMV for life. The infection usually remains latent.

4. CMV REACTIVATION • In the general population, the proportion of people with evidence of previous CMV infection range from 40% to 100%, depending on ethnicity and country of residence. • CMV reactivation develop frequently when T-lymphocytes mediated immunity is compromised, for e.g. organ transplant, lymphoid neoplasm, acquired immunodeficiencies. • Clinically significant HIV related CMV infection is associated with severe immunosuppresion , CD4 <50 cells/mm3

5. CMV AND HIV • In patients with AIDS, CMV is the most common viral opportunistic infection. • CMV disease had a prevalence of 21% to 44% before highly active antiretroviral therapy. • Cytomegalovirus retinitis is the most common form of CMV disease followed by polyradiculopathy and gastrointestinal disease. • The connotation of CMV pneumonia in HIV-infected patients is not clear. • Diagnosis of CMV pneumonia in patients with AIDS is difficult: • the clinical abnormalities are not distinctive , • CMV is likely to coexist with other pulmonary pathogens.

6. TRANSMISSION Transmission : 1. From mother: i) In-uterus (transplacental) ; ii) birth canal secretion-during birth. iii) breast milk 2. From Day-Care-Center through saliva. 3. Commonly from venereal contact, respiratory secretion & fecal-oral route. 4. Iatrogenic- i)Blood transfusion ; ii)Transplant from infected donor.

7. Clinical features SYMPTOMS : • shortness of breath, • dyspnea on exertion • dry, nonproductive cough. EXAMINATION : • The heart and respiratory rates are elevated • Hypoxemia is usually present • Auscultation of the lungs often reveals minimal findings • Chest radiography shows diffuse interstitial infiltrates

8. RADIOLOGY Chest x-ray (CXR) – findings present in most patients. Usually bilateral. CT findings : • Interstitial changes are most common • Alveolar consolidation in ~25% • Ground glass appearance may be present in some • Nodular opacities in ~10% • Pleural effusion in ~30% • Adenopathy in ~10% • Most patients with normal CXR will have findings on CT scan and gallium scan. Differentiation of this infection from PCP on the basis of radiographic findings may not be possible.

9. DIAGNOSIS : CLINICAL+RADIOLOGICAL+ISOLATION OF CMV • Virus isolation : • samples : urine, saliva , blood, BAL and biopsy specimen • Cell culture: human embryo lung fibroblast • (b) DEAFF ( Detection of early antigen fluorescent foci ) : • (c) Histopathology - Cytomegalic inclusions can be recognized from biopsy material by the typical "owl 's eyes appearance “ • (d) Tissue immunofluorescence • (e) Electron microscopy • (f) ELISA, PCR • Serology : • CMV IgM antibodies are detected in primary infection and lasts for 3 - 4 months • CMV IgG is produced early in primary infection and persists lifelong. 

10. Treatment • Valganciclovir : oral or IV formulation . • Alternative for refractory disease : foscarnet, although its use is associated with high rates of renal dysfunction . • Duration of therapy : 2 to 3 weeks. As with other opportunistic infections, the antiretroviral therapy with restoration of the CD4 cell count plays a critical role in preventing recurrences. • Prevention of infection in hiv : Patients with HIV infection who are CMV IgG negative and require blood product support should followed standard guidelines for minimizing the risk of transfusion-related CMV infection.

11. influenza • Influenza viruses are members of the orthomyxoviridae family of which influenza A,B & C constitute three separate genera. Influenza A&B are major human pathogens. • The virions are irregularly shaped spherical particles, • Single stranded RNA viruses, • 8-120 nm dia • lipid envelope with H and N glycoprotein. • H - virus binds to the cell receptor. • neuraminidase - release of virus from infected cells.

12. Influenza in hiv • The clinical presentation of influenza in patients infected with HIV is no different from other patient groups. • The rate of pulmonary complications is similar to that of HIV-negative patients. • The duration and severity of influenza appear to be increased in HIV-infected persons. In addition, owing to immunocompromise , HIV-infected patients may be at increased risk of bacterial complications of influenza. • Only HAART seems to be able to reduce the number of influenza-associated hospitalizations.

13. Routes of transmission and pathology • Transmission occurs via aerosols generated by cough and sneezes , although hand to hand contact, other personal contacts and even fomite transmission may take place. • The initial event in influenza is infection of respiratory epithelium with influenza virus acquired from respiratory secretions of acutely infected individuals. • Cells affected: ciliated columnar epithelium(initially), alveolar cells, mucous gland cells and macrophages. • In infected cells, virus replicates within 4-6 hrs after which the virus is released to infect adjacent or nearby cells. In this way infection spreads from a few foci to a large number of respiratory cells over several hours.

14. Influenza pneumonia : presents in 1 of the 3 different forms. • Primary influenza pneumonia develops when the influenza virus infection directly involves the lungs. Clinically, it presents as an acute influenza episode that does not resolve spontaneously. • Influenza virus affects the tracheobronchial epithelium, leading directly to a decrease in cell size and cilia loss; this in turn predisposes the patients to infection by other bacterial pathogens (secondary influenza pneumonia). Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Clinical signs and symptoms are consistent with classical bacterial pneumonia: cough, purulent sputum, and physical and x-ray signs of consolidation. Gram staining and culture of sputum specimens may determine the aetiology. • Finally, there could be a mixed viral and bacterial pneumonia that is a co-infection with both.

15. Clinical features • Typical symptoms of influenza : Onset is abrupt. • Systemic: feverishness, headaches, myalgias (extremities, long muscles of the back; eye muscles; in children: calf muscles), malaise, prostration • Respiratory: dry/productive cough, dyspnoea, nasal discharge - may be absent in elderly people who may present with lassitude and confusion instead , hypoxemia

16. Physical findings • Fever: rapidly peaking at 38-40°C (up to 41°C, especially in children), typically lasting 3 days (up to 4-8 days), gradually diminishing; second fever spikes are rare. • Face: flushed • Skin: hot and moist • Eyes: watery, reddened • Nose: nasal discharge • Mucous membranes: hyperaemic • Cervical lymph nodes: present • In more severe cases, diffuse rales may sometimes be present. At this stage, x-ray findings show diffuse interstitial infiltrates

17. Work up • Radiography: Early radiographic findings include no or minimal changes. • Later, bilateral symmetrical patchy, nodular or interestitial infiltrates become visible. Focal infiltrates indicate superimposed bacterial pneumonia. • Effusions and lymphadenopathy are also observed.

18. Diagnosis: diagnosed clinically and confirmed in the laboratory . Viral culture - gold standard . Takes 48 to 72 hours . Sputum and nasal washes superior to throat swabs Rapid viral diagnostic tests • immunofluorescence (IF) assays, • enzyme immunoassays (EIA), • polymerase chain reaction (PCR)-based testing. The Human Influenza Virus Real-Time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) - provide results within 4 hours • The sensitivity -72% to 95% and the specificity 76% to 84%. • Best timing : 24-48 hours after the start of the illness.

19. treatment •  Neuraminidase inhibitors (oseltamivir , zanamivir) have been recommended especially when theonset of the symptoms are acute, immunosuppression is severe • Oseltamivir is taken orally (75 mg bid), • zanamivir [Relenza] is taken via an inhalation apparatus (10 mg bid for 5 d). To be effective, these agents must be administered within 40 hours of symptom onset. • Prevention : vaccination (mainstay in immunocompromised). • standard infection control measures : good hand hygiene , contact and droplet isolation to limit nosocomial spread.

20. Prevention • Standardinfectioncontrolmeasures such as good hand hygiene as well as the use of contact and droplet isolation are recommended by the CDC to limit nosocomial spread of infection. • The mainstay for prevention of influenza in immunosuppressed patients should be vaccination. • Two types : • an intramuscular influenza vaccine (inactivated virus or subvirion components) • an intranasal influenza vaccine (attenuated cold adapted donor virus from which reassortants with H and N antigens are generated). • Egg anaphylaxis is a contraindication for both vaccine types.

21. ADENOVIRAL INFECTION : • Adenoviruses are nonenveloped, double-stranded DNA viruses. • There are 51 immunologically distinct serotypes of adenoviruses. • Tend to cause infection throughout the year without a specific seasonal predominance. • Are relatively resistant to chemical and physical agents and to adverse pH conditions and can live for a long time outside the body. • Transmission occurs via aerosolized droplets, direct conjunctival inoculation, fecal-oral spread, or exposure to infected tissue or blood. Neonates may acquire adenovirus infection from exposure to cervical secretions at birth.

22. Adenoviruses are a group of viruses that can infect the membranes (tissue linings) of the respiratory tract, eyes, intestines, and urinary tract.  • Adenoviruses most commonly cause respiratory illness. The symptoms can range from the common cold to pneumonia, croup, and bronchitis. Depending on the type, adenoviruses can cause other illnesses such as gastroenteritis, conjunctivitis, cystitis, and less commonly, neurological disease. • Adenoviral infections affect babies and young children much more often than adults • Who is at risk : Infants and people with weakened immune systems are at high risk for severe complications of adenovirus infection.

23. Adenoviral infection in HIV • Adenovirus pneumonia is uncommon in patients with AIDS. It has been reported in 7.4% of patients with HIV with community-acquired pneumonia but is almost always associated with multiple other pathogens including CMV, herpes simplex virus (HSV) type 2, pneumocystis jiroveci, hepatitis A and B, Epstein Barr virus, Candida albicans, Mycobacterium avium, Mycobacterium tuberculosis, varicella-zoster virus (VZV), enteroviruses etc. . • Because of the prevalence of multiple opportunistic infections, it is difficult to ascribe mortality related to adenovirus infection alone. • Cases of fatal pneumonia have been reported.

24. Range from asymptomatic shedding to fatal disseminated disease • Disease may result from • Primary infection • Reactivation of infection in patient • Reactivation of infection in donor organ

25. diagnosis The diagnosis of adenovirus infection is established by • histology, • viral cultures(gold standard) - Nasopharyngeal aspirates or swabs, throat swabs, and sputum samples are appropriate. • direct immunofluorescence, • electron microscopy, • or enzyme immunoassays.

26. PREVENTION • PREVENTION : Currently, there is no adenovirus vaccine available for the general public.  • To prevent nosocomial outbreaks of adenovirus infections, health care providers should strictly follow infection control practices, including contact and droplet precautions. • Strict attention to infection control practices, including contact and droplet precautions, is effective for stopping health care associated outbreaks of adenovirus infections, such as epidemic keratoconjunctivitis.

27. TREATMENT • Most adenovirus infections are mild and typically require only treatment of symptoms. • There is no specific therapy for adenoviruses. However, cidofovir (a cytosine analog that inhibits DNA polymerase) has been used to treat severe adenovirus infections in people with immunocompromised systems.Because of the risk of nephrotoxicity, this drug should be used with caution. • Two regimens are typically used: 5 mg/kg every 1 to 2 weeks, or 1 mg/kg 3 times per week, the latter being associated with less nephrotoxicity. • Serious adenovirus infections can only be managed by treating symptoms and complications of the infection. 

28. Figure 2.Chest CT scans showing multiple areas of airspaceconsolidation (arrows) within the lungs with peripheral area of ground-glass opacity. A: Bilateral upper lobe consolidation Figure 1.Chest radiograph demonstrating bilateral nodular densities (arrows).

29. Other viruses • Pneumonitis in HIV patients has been reported due to herpes simplex virus, as well as respiratory syncytial virus, and parainfluenza virus type . • These are rare causes of pneumonia in HIV-infected patients, but should be considered when clinicians cannot identify an alternative diagnosis. • Identification of herpes simplex virus in respiratory secretions usually indicates evidence of reactivation in the aerodigestive tract rather than primary pneumonitis, although pulmonary or tracheal infection may rarely occur, especially in the context of endotracheal or nasogastric intubation

30. Viruses have become an important etiology of community acquired and hospital-acquired pneumonia in immunocompromised patients and cause significant morbidity and mortality in this population. • Newer molecular techniques have allowed us to discover new viral etiologies of pneumonia, expanding the spectrum of possible etiologies. • Although new diagnostic tests have become available, there is still a need for a sensitive, specific, cost-effective test that would allow us to perform earlier and faster diagnosis which is the key to a good clinical outcome. • Treatment options for viral pneumonia are limited • Therefore, preventive measures such as vaccination, preemptive, and prophylactic antivirals as well as infection control measures are the cornerstone of preventing disease transmission to susceptible hosts and decreasing the morbidity and mortality rates associated with viral pneumonia

31. toxoplasma • Toxoplasmosis is caused by infection with the protozoan Toxoplasmagondii, an obligate intracellular parasite • Toxoplasmagondiican induce systemic disease with multiple sites of infection, or can infect one organ preferentially. • Pulmonary toxoplasmosis, estimated to account for 4% of all cases of pneumonia in AIDS patients , is the second or third most frequent form of toxoplasmosis, after toxoplasmic encephalitis • T gondii is one of the most common causes of chronic infection with an intracellular organism in humans. A chronically infected individual who develops defects in cell-mediated immunity is at risk for reactivation of the infection.

32. Life cycle

33. Clinical presentation • Reactivation of a chronic infection manifests primarily as toxoplasmic encephalitis. • This disease is an important cause of focal brain lesions in HIV-infected patients. HIV-infected patients may develop extracerebral toxoplasmosis with or without concomitant encephalitis. • Ocular and pulmonary disease are the most common presentations in patients with extracerebral toxoplasmosis • Pulmonary toxoplasmosis occurs mainly in patients with advanced AIDS (mean CD4+ count of 40 cells/µL ±75 standard deviation) and primarily manifests as a prolonged febrile illness with cough and dyspnea. • Pulmonary toxoplasmosis may be clinically indistinguishable from P(carinii)jiroveci pneumonia • A highly lethal syndrome of disseminated toxoplasmosis that consists of fever and sepsis like syndrome with hypotension, disseminated intravascular coagulation, elevated lactic dehydrogenase , and pulmonary infiltrates has been described in HIV-infected patients.

34. DIAGNOSIS : Directdetection: demonstration of T gondiiorganisms in blood, body fluids, or tissue.  • T gondii may be isolated from the blood via either inoculation of human cell lines or mouse inoculation. Mouse inoculation may require a longer time to yield results and also is likely to be more expensive. • Polymerase chain reaction assay testing on body fluids, including CSF, amniotic fluid, bronchoalveolarlavage fluid, and blood, may be useful in the diagnosis. Indirect detection : Detection of immunoglobulin G (IgG) is possible within 2 weeks of infection using the enzyme-linked immunosorbent assay (ELISA) test, the IgG avidity test, and the agglutination and differential agglutination tests.

35. Preventive measures • Immunocompromised patients should avoid the following: • Raw or undercooked meat or eggs • Unpasteurized milk • Contact with cat feces, including changing of cat litter trays • If handling raw meat, touching eyes or other mucous membranes should be avoided, and hands should be washed thoroughly afterward • Meat should be cooked to a temperature of 74° to 77°C (165°-170°F) • All raw fruits and vegetables should be washed before eating • Gloves should be worn when working with sand or soil, and, if not, hands should be washed thoroughly after contact

36. treatment • Ist line therapy : combination of pyrimethamine (a dihydrofolate reductase inhibitor) plus sulfadiazine (a dihydrofolate synthase inhibitor) • Duration:6weeks • clindamycin may be substituted if the patient cannot tolerate sulfadiazine. • Prophylaxis: patients should receive secondary prophylaxis until their CD4 count is greater than 200 cell/mm3 for over 6 months. Prophylaxis with double strength TMP/SMX once daily in HIV-positive patients with CD4 counts less than 100 cell/mm3 has been shown to reduce the risk of CNS toxoplasmosis, and likely also prevents pulmonary disease .

37. Strongyloides • Strongyloides stercoralis is a soil-dwelling nematode worm,common in the wet tropics of South America, Africa, and SouthEast Asia. • The larval forms of this nematode penetrates the skin of the host and circulate widely before maturing and settling in the small intestine. • In patients with abnormalities of cell-mediated immunity, strongyloides hyper infection syndrome may occur producing pulmonary infection that may manifest as asthma, chronic bronchitis , haemoptysis , eosinophilia and pulmonary infiltrates. • Sputum cytology is a useful test for strongyloidiasis in patients with steroid-dependent unexplained lung disease or lung shadows.

38. STRONGYLOIDES IN HIV • Strongyloides stercoralis is surprisingly rare in HIV infected individuals, even in areas highly endemic for both HIV and strongyloides. • Indeed, many patients with HIV who experience strongyloides superinfection syndrome have other classic risk factors, including receipt of corticosteroids, severe wasting, or HTLV-I co-infection. • Despite its rarity, clinicians should consider the diagnosis of strongyloidiasis in an HIV infected patient who presents with pneumonitis, or gram negative sepsis with associated meningitis. • Identification of strongyloides larvae on a centrifuged BAL specimen is diagnostic; eosinophilia is variably present, and its absence does not exclude the diagnosis. • When strongyloides is identified in the lung, disseminated disease has occurred by definition; treatment should be with extended courses of ivermectin plus albendazole.

39. cryptosporidiosis and microsporidiosis • Although predominantly involving the gastrointestinal tract, both cryptosporidiosis and microsporidiosis can rarely be found in the lung and lead to pulmonary disease. • Diagnosis is through direct visualization of the organism on respiratory secretions or histopathology, using appropriate stains—modified acid-fast for cryptosporidiosis—and the modified trichrome stain for microsporidiosis. • As antimicrobial treatment for these conditions is suboptimal, improving immune function with antiretroviral therapy is the preferred strategy.

40. Pulmonary neoplasia in HIV • KAPOSI SARCOMA • BRONCHOGENIC CARCINOMA • HODGKIN & NON-HODGKIN LYMPHOMA

41. Do the people infected with HIV have an increased risk of cancer: • Yes, people infected with HIV have a substantially increased risk of some types of cancer compared with uninfected people of the same age. Three of these cancers are known as “AIDS defining cancers”: • Kaposi’s sarcoma • Non-hodgkin lymphoma • Cervical cancer • A diagnosis of any one of these cancers marks the point at which HIV infection has progressed to AIDS • People infected with HIV are several thousand times more likely than uninfected people to be diagnosed with kaposi sarcoma, at least 70 times more likely to be diagnosed with non-hodgkin lymphoma

42. Why do people infected with HIV have a higher risk of cancer • Infection with HIV weakens the immune system and reduces the body’s ability to fight infections that may lead to cancer . Many people infected with HIV are also infected with other viruses that cause certain cancers. • Human herpes virus 8 HHV also known as Kaposi’s sarcoma associated herpes virus, is the cause of kaposi sarcoma • Epstein barr virus causes some subtypes of nonhodgkin and hodgkin lymphoma

43. Kaposi sarcoma • Kaposi sarcoma (Kaposi's sarcoma, KS) was described initially in 1872 by a Hungarian dermatologist, MoritzKaposi . • It is a spindle-cell tumor thought to be derived from endothelial cell lineage. • This condition carries a variable clinical course ranging from minimal muco-cutaneous disease to extensive organ involvement. • Kaposi sarcoma can be primarily categorized into four types: epidemic of AIDS-related, immuno-compromised, classic or sporadic, and endemic (African). • Thoracic disease is found in about 45% of patients with cutaneous AIDS-related KS, and in about 15% of patients without mucocutaneous involvement. Currently, after the introduction of HAART therapy, pulmonary involvement has probably become much less frequent.  • Kaposi's sarcoma can recur easily, despite treatment and remission. • If the lesions remain isolated on the skin, Kaposi's sarcoma isn't a life-threatening illness. If, however, it attacks the inner organs, including the lungs, brain, and gastrointestinal tract, Kaposi's sarcoma can be fatal.

44. Pathology and pathogenesisHHV8 & Host immunosuppression • There is evidence from epidemiologic, serologic, and molecular studies that KS is associated with human herpes virus type 8 (HHV8) infection . In addition, other agents such as cytokine-induced growth factors have been linked to the development of the disease. • The disease starts as a reactive polyclonal angioproliferative response towards HHV-8, in which polyclonal cells change to form oligoclonal cell populations that expand and undergo malignant transformation .

45. The histopathologic process of the disease is believed to start in the sub epithelial connective tissue, extending in the direction of the epithelium. • A developed lesion consists of interwoven bands of spindle cells and vascular structures grouped in a network of reticular and collagen fibers. • Erythrocytes are seen within these vascular structures and interspersed between spindle cells. • The vascular component appears as small capillaries or slit-like spaces between the spindle cells .

46. Clinical presentation KS may involve the lung parenchyma, bronchial tree, and pleural surfaces.  Although pulmonary involvement is occasionally asymptomatic and found incidentally on radiographs or during bronchoscopy performed for other purposes, patients typically are symptomatic. • Cough • Fever • Dyspnoea • Night sweats • Haemoptysis • Stridor

47. RADIOGRAPHY Xray findings: • Middle to lower lung zones reticular opacities • Parenchymal nodules • Consolidation • Pleural effusion • Mediastinal or hilar adenopathies Ct findings : • Thickening of peribronchovascular interestitium • b/l ill defined and irregular nodular opacities • Interlobular septal thickening

48. diagnosis • The diagnosis of pulmonary involvement in KS usually can be made by a combination of clinical, radiographic, and laboratory findings, together with the results of bronchoscopy and transbronchial biopsy  • KS usually manifests dermatologically as pigmented macules, plaques, papules, or nodules, but subcutaneous nodules may arise without visible skin pigmentation. The differential diagnosis for cutaneous KS lesions includes hemangiomas, nevi, dermatofibromas, and bacillary angiomatosis • Performing a punch biopsy will help in making the correct diagnosis • Bronchoscopy may reveal endobronchial KS in the absence of radiographic findings. Endobronchial lesions generally are diagnosed by appearance and biopsy of such lesions is attempted rarely because of concern about bleeding. 

49. ACTG Staging Classification for AIDS-Associated Kaposi Sarcoma • Tumor (T) -- T0 (good risk): Confined to skin and/or lymph nodes and/or minimal oral disease* --- T1 (poor risk) : Tumor-associated edema or ulceration, and/or Extensive oral KS, and/or Gastrointestinal KS, and/or KS in other non-nodal viscera • Immune system (I) ---I0 (good risk): CD4 cells >=200/mL ---I1 (poor risk): CD4 cells <200/mL • Systemic illness (S) ---S0 (good risk): • No history of OIs or thrush • No "B" symptoms # • Karnofsky performance status >=70 • S1 (poor risk): • History of OIs or thrush, and/or • "B" symptoms present, and/or • Karnofsky performance status <70, and/or • Other HIV-related illness (eg, neurologic disease, lymphoma)

50. treatment • Most forms of KS will regress with the initiation of HAART, with response rates of 60%-80%. • LOCAL : Cosmetically disturbing lesions should be treated early and, if limited in number, may be appropriate for local therapy. Electrodesiccation and curettage, cryotherapy, or by surgical excision. Radiation therapy is the most effective therapy for localized areas of skin . • CHEMOTHERAPY: In epidemic KS, the already profoundly depressed immunologic status of the host limits the therapeutic usefulness of systemic chemotherapy. Systemic chemotherapy studies in epidemic KS have used as single agents or in combinations - liposome-encapsulated anthracyclines , doxorubicin, bleomycin, vinblastine, vincristine, etoposide, paclitaxel, and docetaxel • BIOLOGICTHERAPY: Interferon-alfa in combination with antiretroviral agents should be considered for the treatment of patients with slowly progressive or minimally symptomatic KS.