Opportunistic infections

In western world widespread use of HAART (highly active antiretroviral therapy) has led to dramatic decline in the incidence of commonly occurring opportunistic infections (OIs) seen in pre-HAART era, now this is being replicated in developing countries like India. Opportunistic infection may be the presenting feature of HIV infection or it may develop during course of diagnosed HIV infection. Various OIs can complicate course of untreated as well as treated HIV infection. Tuberculosis,

diarrhoeal diseases and candidiasis are the commonest OIs in Indian patients. Other life-threatening OIs like Pneumocystis jiroveci pneumonia, toxoplasmosis, cryptococcal infections, CMV disease and herpes virus infections requires high index of suspicion and proper management for successful outcome from the disease.

Table 1: CD4 T cells cut-offs for expected opportunistic infections ^*

CD4 cells/mm3	Opportunistic infections
< 200/mm3	Pneumocystis pneumonia, progressive multifocal leukoencephalopathy
< 100/mm3	Cerebral toxoplasmosis, cryptococcosis, HIV encephalopathy, disseminated herpes simplex, chronic cryptosporidiosis, candidial oesophagitis
< 50/mm3	Cytomegalovirus retinitis, cryptosporidiosis, atypical mycobacteriosis

^* These CD4 counts are only reference values; exceptions are always possible. No CD4 cut-off for Kaposi’s’ sarcoma, pulmonary tuberculosis, herpes zoster virus, bacterial pneumonia and lymphoma

Pneumocystis Pneumonia (PCP)

Pneumocystis pneumonia (PCP) is an AIDS defining illness, commonly seen in patients with CD4 < 200 cells/mm³. Although incidence of PCP is decreasing in ART era, it is still one of the most frequently occurring OIs in HIV-infected patients in India. PCP may be the first presenting illness in HIV infected patients or it may occur as a part of immune reconstitution inflammatory syndrome following ART. It is a life-threatening medical emergency requiring high index of suspicion for diagnosis. Early diagnosis and treatment are essential for successful outcome.

Signs and Symptoms

PCP almost always present with pulmonary symptoms. Dry cough, fever and exertional dyspnoea (ask patient specifically) constitute classical triad of PCP symptoms. Onset is insidious and progress is gradual. Hypoxia at rest or on exertion is present. Additional clues on examination are oral thrush and weight loss.

Diagnosis

Definitive diagnosis requires demonstration of organisms either in sputum (sensitivity 56%) or BAL (sensitivity 95 %). Chest x-ray typically shows bilaterally symmetrical perihilar interstitial infiltrates fading towards periphery, usually sparing the apex.

Treatment

Treatment should be initiated immediately on clinical suspicion even without establishing definitive diagnosis. The drug of choice is co-trimoxazole (trimethoprim 15-20 mg/kg/day and sulphamethoxazole 75-100 mg/kg/day). Treatment may be initiated with oral co-trimoxazole when i.v. formulations are not available. Treatment should be continued for 21 days; however it may be curtailed to 14 days with mild disease and rapid response. Patients with moderate to severe disease (PO₂ < 70 mm Hg or A-a gradient > 35 mm Hg) should receive corticosteroids (prednisolone 40 mg bid x 5 days, then 40 mg qd x 5 days, then 20 mg/day till completion of treatment) to reduce inflammation because of bursting of pneumocysts in alveoli. If patient fails to respond within 5-7 days, diagnosis of PCP should be reconfirmed and other co-infections should be ruled out. Drug toxicity (haematological, skin, renal and hepatic) should be monitored closely. Alternative regimens available in case of co-trimoxazole allergy or intolerance are clindamycin + primaquine, i.v. pentamidine, trimethoprim + dapsone and atovaquone. All these regimens are less effective than co-trimoxazole.

Prophylaxis

Primary prophylaxis is recommended for following patients: CD4 < 200 cells/mm³, previous history of PCP, patients with prolonged (> 2 weeks) fever and thrush, patients with CD4 count between 200-250 cells/mm³ and not following regularly. Secondary prophylaxis is to be continued life-long, but may be discontinued in patient on HAART and maintaining CD4 > 200/mm³ for more than 3 months. Co-trimoxazole DS tablet once daily is more effective than thrice weekly regimen. It also provides protection against toxoplasmosis and other bacterial infections.

Toxoplasmosis

Toxoplasma gondii is an obligate intracellular protozoan. Environmental or food exposure to oocysts leads to human infection. Disease manifests usually with immunosuppression and is due to reactivation of latent infection. Primary infection is very rare. Neurotoxoplasmosis is the most common OI involving CNS, occurring with CD4 < 100 cells/mm³ and accounts for 50-60% of CNS mass lesions.

Toxoplasma manifests primarily as encephalitis in AIDS patients. Focal neurologic signs, seizures, cranial nerve deficits, confusion, lethargy and rapid mental status decline are common presenting features.

Diagnosis

Between 97-100% of HIV-infected patients with toxoplasma encephalitis have anti-toxoplasma IgG antibodies present in serum (absence of antibodies makes the diagnosis of toxoplasmosis unlikely). Contrast CT or MRI brain reveals multiple, bilateral, hypodense, contrast-enhancing focal brain lesions involving the basal ganglia and hemispheric corticomedullary junction. Diagnosis is presumptive on clinical and radiological findings, and response to therapy establishes diagnosis.

Treatment

Preferred regimen for induction is combination of pyrimethamine (100-200 mg loading dose, then 50-100 mg od) along with sulfadiazine (4-8 gm/day) plus leucovorin (10-20 mg/day) for 6 weeks. For patients intolerant to sulphadiazine, alternative regimen is pyrimethamine (same dose) plus clindamycin (600 mg i.v. or p.o. q 6 h) plus leucovorin for six weeks. Other useful agents are azithromycin 1200 mg qd or atovaquone 1500 mg bid with pyrimethamine in above dosage. After successful induction patients should receive pyrimethamine (25-50 mg qd) with sulphadiazine (2-4 gm/day) with leucovorin as maintenance therapy. Alternative agents are clindamycin, atovaquone, and azithromycin along with pyrimethamine. Co-trimoxazole prophylaxis given for PCP is sufficient to prevent reactivation of toxoplasmosis. Alternative regimen is dapsone (50 mg od) with pyrimethamine (50 mg per week) with leucovorin (25 mg per week). Primary or secondary prophylaxis can be discontinued when CD4 > 200 cells/mm³ for more than 3 months on ART.

Candidiasis

Initial episodes of mucosal candidiasis are invariable results from overgrowth of Candida albicans, a commensal in human mouth, GI tract and vagina. Other  Candida species that can cause oropharyngeal candidiasis (OPC) include C. tropicalis, C. glabrata, and C. krusei.Oral and oesophageal Candidiasis usually present as altered taste sensation, burning pain in mouth and odynophagia. On clinical examination characteristic white, curd-like plaque (pseudomembranous) that can be easily scraped off or erythematous patch (atrophic) over oral mucosa or angular cheilitis.

Diagnosis

Diagnosis of OPC can be easily arrived by clinical appearance. Microscopic examination of a wet mount smear is useful for evaluation of yeast and/or pseudohyphae. Culture from mucosal lesions helps to identify Candida spp. and allows sensitivity testing if response to therapy is poor. Diagnosis of candidial oesophagitis is based on clinical symptoms and presences of OPC on examination. Endoscopy is often required with unusual presentations.

Treatment

For oropharyngeal candidiasis clotrimazole oral troche or nystatin (oral) or fluconazole (100 mg/day) for 14 days is preferred treatment. Alternative regimens include dose escalation with fluconazole, itraconazole (oral solution, not capsule due to poor bioavailability), i.v. amphotericin B and caspofungin.

For oesophageal candidiasis preferred treatment is either fluconazole (200 mg/day) or itraconazole (200 mg/day oral or i.v.) to be given for 14-21 days. Intravenous therapy may be required in patient with severe odynophagia. Alternative regimens include i.v. amphotericin B, lipid amphotericin B formulations, caspofungin and voriconazole. ART is most effective treatment for recurrent disease.

Cryptococcal Meningitis

Cryptococcal meningitis is caused by fungus Cryptococcus neoformans. Infection is acquired by inhalation of fungus, but pulmonary infections are usually asymptomatic. Meningitis usually occur with CD4 < 100 cells/mm³. Headache (70-90%) is the most common presenting symptom. Fever (60-80%), malaise (76%), photophobia and other visual disturbances (6-18%), seizures (5-10%), nausea, altered mental status and seizure are other common symptoms. Signs of meningeal irritation are often absent.

Diagnosis

CSF routine (25-30%) and microscopic examination may be normal except raised intracranial pressure (ICP). CSF cryptococcal antigen test is positive in > 99% of AIDS patients with cryptococcal meningitis. CSF India ink preparation is less sensitive (60-80%) in diagnosis.

Treatment

Amphotericin B is the drug of choice. Induction therapy with amphotericin B deoxycholate (0.7-1 mg/kg/day i.v.) with or without flucytosine (100 mg/kg/day p.o.) for two weeks is preferred. This should be followed by consolidation with fluconazole 400 mg/day for 8 weeks. In patients intolerant to amphotericin B, alternative regimens include fluconazole (400-800 mg/day p.o.) with 5-fluorouracil (FC) for 6 wks or lipid formulations of amphotericin B (4-5 mg/kg/day i.v.) for 6-10 wks. This should be followed by fluconazole (200 mg/day p.o.) as maintenance therapy, which is superior to amphotericin B and itraconazole. Maintenance therapy may be discontinued in patients on ART and maintaining CD4 > 200/mm³ for more than 6 months and patient is asymptomatic.

Cryptosporidiosis

Cryptosporidium parvum is an intracellular protozoan parasite. Environmental oocysts can survive for many months. Person-to-person transmission among family members and close contacts can occur because of relatively low (< 1000 oocysts) inoculum dose.

Typical symptoms are acute, subacute or chronic profuse, watery diarrhoea often associated with cramps, nausea and vomiting. Fever occurs in one-third of patients.

AIDS patients can have asymptomatic carriage (4%), self-limiting diarrhoea (29%), chronic diarrhoea (60%), or fulminant diarrhoea (8%). The chronic and fulminant forms are seen almost exclusive with CD4 < 100 cells/mm³. Microsporidia, Cyclospora, Isospora, MAC, Giardia, and Clostridium difficile can produce similar symptoms.

Diagnosis

Examination of stool, duodenal aspirates or bile smears by modified acid-fast stain is the mainstay of diagnosis. Repeated examinations may be required because of intermittent shedding of oocysts. Immunofluorescence, Giemsa and methenamine-silver stains have also been used.

Treatment

ART with immune reconstitution is the only treatment that controls persistent cryptosporidiosis. More than 95 drugs have been tried and none is consistently useful. Nitazoxanide, paromomycin, azithromycin, octreotide and atovaquone have been used with limited success. Supportive treatment with fluid replacement, antiperistaltic agents (loperamide, atropine/diphenoxylate, and octreotide) and nutrition supplementation are required.

CMV diseases

In HIV infected patients CMV infection occurs as a part of reactivation of latent infection, usually with CD4 < 50 cells/mm³. Eye, lungs, GI, liver and gall bladder are common involved organ with CMV in HIV patients. Multiple organ involvement is seen in advanced HIV infection.

CMV Retinitis

CMV retinitis is the most common cause of visual loss in AIDS patients. Patient may be asymptomatic or present with floaters, field defects, scotomas or decreased acuity. Diagnosis is usually made by fundoscopic examination. Fundus usually shows perivascular yellow-white retinal infiltrate with or without intraretinal haemorrhage (‘cottage-cheese and ketchup’). Lesions may be unilateral or bilateral, single or multiple. Full thickness retinal necrosis is associated with irreversible loss of vision.

Treatment

Goals of therapy are to prevent further visual loss, control the disease with ART and prevent relapse. Visual loss prior to therapy is usually irreversible. Choice of treatment is based on location of lesions. For vision threatening lesions intraocular ganciclovir implant with oral valganciclovir is preferred treatment. Implant requires replacement every 6-8 months in absence of immune reconstitution. Peripheral lesions may respond to ART alone. Maintenance therapy is to be continued for life-long for patients not on ART. Maintenance therapy may be discontinued if CD4 cell count is > 100-150/mm³ for more than 6 months and there is no evidence of active disease.