2002 Mar - A Series of Uncommon Chest Infections in Non – HIV Patients
Dominic Tsang, Department of Microbiology, QEH; Wong Ka Chun, Respiratory Medical Department, KH; Stephanie Chu, Department of Medicine, QEH
Case 1
The patient was a 52 years old gentleman. He complained of an episode of one mouthful of haemoptysis, mild cough with small amount of sputum. He had no fever and night sweating. He didn't report symptoms of chest pain, leg swelling, and weight loss.
He had undergone cholestectectomy 10 years ago, and partial gastrectomy 20 years ago; otherwise, his past health was unremarkable.
He was a lifetime nonsmoker and nondrinker. He was a businessman with an unremarkable travel history.
Physical Examination and Blood tests were normal and his HIV status was negative. Sputum examinations for microscopy, AFB, cytology, culture, and fungus were unrevealing.
His Chest X-ray on presentation showed patchy shadow in right mid-zone CT thorax (Fig 1) showed a cluster of small nodules intermixed with some patchy reticular lung density in the apical segment of the right upper lobe. The largest nodule measures 9 x 8mm, it shows soft tissue density with a maximal density of 25.6, no contrast enhancement, no calcification.
Fibreoptic bronchoscopy showed necrotic material at one of the subsegment of right apical lower segment. Bronchial aspirate for culture and microscopy, AFB, cytology, and fungus were negative. Bronchial biopsy showed necrotic tissue debris admixed with reactive bronchial epithelium and lung parenchyma. There were multiple aggregates of fungal hypae. They possessed irregular width and occasional right angle branching. The histological diagnosis was Mucormycosis.
Surgery was advocated to him for the potential risk of fatal haemoptysis, yet the patient declined. Intravenous amphotericin B, totally 2026 mg, was given. Radio logically, RMZ shadow resolved. Flexible bronchoscopy repeated showed no necrotic tissue in his right apical lower segment. Interval CXRs remained static in the subsequent follow-ups up to half year posttreatment; however, the patient had occasional mild haemoptysis after treatment.
Mucormycosis infection due to Zygomycetes is known as Zygomycosis. Mucor is a member of the order Mucorales. It is an aerobic organism in soil of worldwide distribution.
The fungi occur in air, soil, and food. It is filamentous consisting of board irregular hypae of 15 to 20 /-lm in diameter, mostly non-septated and right angle branching.
Pathogenesis
Airborne infection is acquired by inhalation of spores (3 to 6 /-lm in diameter) into paranasal sinuses, lower airways, and alveoli. As the fungi are aerobic, they have a special predilection for nasal sinuses and lungs. Other routes of acquisition include ingestion and direct contact by trauma.
Similar to Aspergillus, Mucorales characteristically spreads in the tissues by. vascular invasion, since the blood vessels are the best source of oxygen. The invasion of blood vessels by hyphae leads to arterial thrombosis, tissue infarction, and necrosis, whereas venous invasion causes bleeding
(haemoptysis in lung).
Increased susceptibility is observed in patient with diabetic ketoacidosis, organ transplant recipients, patients undergoing dialysis :t receiving Desferrioxamine therapy, and neutropenic patients with haematological malignancy. Mucormycosis is rare in patients with AIDS, possibly reflecting the relative importance of innate immunity against this infection.
Clinical Manifestations
Mucormycosis has different clinical forms; namely, rhinocerebral, pulmonary, and disseminated Mucormycosis. Other rare manifestations include gastrointestinal, and cutaneous. Pulmonary mucormycosis commonly involves the upper lobes with better aeration. The typical clinical picture is a profoundly ill neutropenic patient with unremitting fever despite broad-spectrum antibiotics, progressive infiltration as shown on chest X-ray, and rapidly deteriorating respiratory failure.
Findings on chest X-ray include patchy consolidation, single or multiple areas of rounded pneumonia of increasing size and number, and cavitating lesion. The actual extent of pulmonary involvement can be much greater than that shown in chest X-rays, since the vasoinvasion causes tissue necrosis, which may not be apparent on X-ray.
The overall survival rate of pulmonary mucormycosis is 44%, depending on underlying predisposing conditions and extent of the lesion.
Diagnosis
Serology currently has no place in diagnosis.
Members of Mucorales are constant inhabitants of the environment, skin, discharges & sputum. It can be easily isolated from patient specimens such as discharges, scrapings and biopsy material. Diagnosis can neither be established based on culture alone nor discarded as contaminants easily. All forms of evidence have to be correlated for an accurate diagnosis.
The yield in sputum is low if the specimen is homogenized before culture inoculation. This dicing procedure destroys the aseptate fungus and decreases the sensitivity of sputum culture. Because of the ubiquitous nature, direct demonstration of the fungal elements in patient specimens is more meaningful than culture. Demonstration of tissue invasion by hyphae in a biopsy specimen is the most specific test for disease
Differential diagnosis of vascular involvement in tissue invasion includes Aspergillus spp. and Pseudomonas spp. infection that can only be differentiated with certainty by culture.
Treatment
Early diagnosis, a high index of suspicion and prompt diagnosis by aggressive investigation such as tissue biopsy, significantly affects the treatment outcome.
Early and repeated surgical debridement of all grossly involved tissue is important for local control of the condition, especially in rhinocerebral, pulmonary, and cutaneous mucormycosis, and early resection of the pulmonary lesion is often necessary to prevent severe haemoptysis.
Amphotericin B is the most reliable anti-fungal agent that is effective against mucormycosis. Although the in vitro sensitivity is variable from isolate to isolate, amphotericin B is clinically effective. The recommended dose is 1 mg/kg/d, but a dosage of up to 1.5 mg/kg/d may be needed for serious infection.
The duration of treatment is between 3 to 6 weeks with a total dose of 2.0 to 4.0g administered, depending on the clinical response, underlying disease, and toxicity.
Azoles have no consistent activity against mucormycosis. The importance of correcting or controlling the underlying predisposing condition cannot be over-emphasized.
Fig 1. CT Thorax of Case 1
Case 2
The patient was a 67 years old retired van driver gentleman. He had been followed by the Government Chest clinic until new RUZ and LMZ shadowing was detected on his CXR (Fig 3).
He had known bilateral bronchiectasis since the age of twenty, with chronic cough and purulent sputum of approximately 100ml per day. All along he had no haemoptysis. He reported weight loss of 14 pounds within the past one year before adnission. He was a smoker, 1 pack per day, and a social drinker. Travel history was unremarkable. Physical examination revealed signs of consolidation
in RUZ.
Blood tests were unremarkable except mild normochromic normocytic anaemia (Hb 10.2 g/dl). Fungal Antibody assay, by Counterimmuno-electrophoresis, was positive for Histoplasmosis, Blastomyces, and Candida. Antibody for HIV I & 2 were negative.
Sputum examination for AFB, smear, cytology, and culture were negative. Blood culture was negative.
Fibreoptic bronchosopy showed purulent secretion at apico-posterior segment bronchus of right upper lobe bronchus. Transbronchial biopsy of the said segment showed focal fibrosis. Bronchial aspirate for AFB and cytology were negative. Bronchial aspirate for fungal culture showed Penicillium marneffei.
Patient was treated by IV amphotericin B; totally one gram of amphotericin B was given. Clinically, sputum volume and purulence improved after anti-fungal. CXR also showed improvement.
Penicillium marneffei
Fungal species of the genus Penicillium are abundant in nature, and many are common laboratory contaminants. Of the more than 200 identified species of the genus Penicillium, P marnefJei is one of the few species cause infections in human, and it is the only dimorphic species.
Epidemiology
The endemic areas for the organism are Burma, Cambodia, southern China, Indonesia, Laos, Malaysia, Thailand, and Vietnam. In these endemic areas, systemic infections with this organism have become very common and now represent one of the most frequent AIDS-defining opportunistic infections in this region, affecting up to 20% of patients in northern Thailand.
Environmental studies so far fail to ascertain the primary source.
The organism can causes infection in persons who are apparently immunologically competent, however, in immunosuppressed patients, especially those with HIV infection, disseminated infections occur much more frequently.
Clinical Features -- Healthy Hosts
Asymptomatic infections occur in healthy individuals.
The likely route of infection in most cases is inhalation of P marnejjei spores. Patients with localized bronchopulmonary disease, with or without adenopathy, have a been reported (like our patient). Cavitatory lung disease also occurs. Chronic cervical lymphadenitis resembling tuberculosis has been described.
Disseminated infections occur in normal hosts as wel!. Hepatosplenomegaly, adenopathy, fever, weight loss, and skin lesions are common findings in humans with disseminated P marnefJei.
Immunocompromised Host and HIV Hosts
85.7% HIV-negative patients had underlying immunosuppressing conditions, eg corticosteroid or cytotoxic therapy. (J Clin Microbiol 2001;39:4535-4540). P. mameffei occurs late in the course of HIV infection. CD4+ cell count at the time of the diagnosis of P. mameffei was consistently less than 50 cells/m!. Clinical presentation, though not specific, included fever (in 99% of the patients), anemia (78%), pronounced weight loss (76%), generalized lymphadenopathy (58%), hepatomegaly (51%), and skin lesions – most commonly papules with central necrotic umbilication were seen in 71% of the patients.
Wong et al reported a local study of P mameffei infection in eight HIV and seven non-HIV subjects (J Clin Microbiol 2001; 39:4535-4540). The non- HIV subjects were immunocompromised to a certain extent, three were patients with autoimmune disease, two had haemic malignancy, and one had diabetes mellitus. Presenting symptoms were similar in the two groups. The time for diagnosis was much shorter in the HIV-infected group (1 weeks) than the HIV-negative group (5.5 weeks). The attributable mortality was lower in the HIV-infected group (12.5%) than the HIV-negative group (28.5%).
Diagnosis
Serology: Antibody and Antigen Detection
The sensitivity of antibody detection depends on antigen used, assay method and patient characteristics. Variable antibody response in immunocompromised might affect the detection. Moreover, pre-existing antibody in high endemicity areas also influence the interpretation of positive serology result. Newer antibody detections involve highly purified and characterized antigen to improve reproducibility and specificity.
Antigen detection tests may be more effective than diagnosing penicilliosis, because the disease often immunocompromised HIV-infected patients who is antibody against the fungus.
antibody testing for occurs in severely unable to produce
Use of antibody and antigenemia tests concurrently increased the sensitivity.
Mannoproteins (MP 1p) are structural components of fungal cell walls. Mp 1P of PM (antigen) and its antibody detection in patients with P Marneffei were studied. (JCM 1999; 37:981-6) Antigen was detected in 17 of 26 serum specimens (65%). Combined with antibody testing, it was positive in 23 patients with P Marneffei (88%) and negative in all 85 controls' sera (PPY: 100%; NPY 96%).
The prognostic value of the antigenemia tests has yet to be determined. P marneffei antigen can also be used to follow the progress of disease.
Diagnosis for P Marnejfei by Urine Antigen
Desakorn et al (JCM 1999; 37: 117-2)used FITC-labeled rabbit hyperimmune immunoglobulin in 33 patients (culture proven) and 300 controls (52 healthy, other hospitalized).
Antigen was detected in all patients with P marneffei at high titre. Sixtyseven (27%) hospitalized and 3 (6%) healthy controls were assay positive. At a cut-off of 1:40.
(Sensitivity = 97% and Specificity= 98%. pry: 84%; NPY 99.7%).
Histopathological Diagnosis
Diagnosis can be established by histopathologic recognition of the fission.yeast-like form of P marnejjei in tissue. However, this can be a challenge because P marneffei and H capsulatum are very similar in early cases.
Culture
Culture reliably identifies P marnefJei by the following features: Critical factors in detection of Fungaemia are adequate volume of blood sampled, adequate blood to broth ratio, aerobic incubation, appropriate incubation temperature (27-30°C for mold, 37 °C for yeast), length of incubation, suitable media used, and specimen processing (Lysis centrifugation best for dimorphic fungi).
Therapy
There were a few reports on treatment of Penicillium marneffei in non-HIY / immunocompetent patients. In the two cases with normal immunity reported by Jayanetra, they were successfully treated by amphotericin B. The infection in HIY patients is associated with a high mortality rate if timely treatment is not given. The standard treatment is intravenous amphotericin B (0.6mg/kg/day) for 2 weeks followed by 10 weeks of oral itraconazole in 2 divided doses of 200mg/day. Sirisanthana et al conducted an open label nonrandomized study to evaluate the efficacy and safety of treatment with this regimen. Of the 74 HIV-infected patients with disseminated P. marneffei infection, 71 (97.3%) responded to the treatment. Fungaemia cleared after 2 weeks in all 65 patients. By the end of two week, only 12 patients remained febrile. No patient remained febrile by the end of 4 weeks. There was no serious adverse reaction that required adjustment in the administration of the drug.
Secondary prophylaxis
Generally, in patients with very low CD4+ cell counts (ie,
Case 3
The patient was a 42 year old man who had a past history of Hepatitis B cirrhosis and nasopharyngeal carcinoma with radiotherapy in 1995. He presented to our unit with productive cough and fever. Chest X-rays showed left pleural effusion and sputum culture grew MRSA (WBC ++). Pleural tapping showed exudative effusion. Culture, cytology and AFB smear of pleural fluid were all negative.
Pleural biopsy did not show any evidence of malignancy or granuloma. He was treated with vancomycin with clinical improvement.
He continued to have symptoms of coughing in his subsequent SOPD follow-up despite radiological improvement. However, he was also noted to have an increasing right chest wall mass over the 6th rib along the mid-clavicular line and was readmitted for further investigations six months later.
Baseline investigations including CBP, liver and renal function were all unremarkable. Sputum culture, AFB and cytology were all negative. CXR showed right lower zone haziness (Fig 1). CT thorax (Fig 3) showed multiple low density soft tissue masses with rim enhancement in the chest walls along the ribs bilaterally which suggested the existence of abscesses. There were also similar masses in paraspinal regions and back muscles with adjacent bony erosion. In addition, there were lytic lesions in T 12 and L1 vertebral bodies. There was splenomegaly as well as bilateral pleural effusions and ascites.
Incision and drainage of chest wall abscess was done. Histology showed suppurative granulomatous inflammation and numerous endosporing spherules with foci of vasculitis. Features were consistent with coccidioidomycosis.
Enquiry into the travel history revealed that Mr. Wong had lived and worked in California for 2 years, having moved back to Hong Kong shortly before the onset of his symptoms.
Further Investigations:
• Autoimmune markers –ve
• Antibodies to aspergillus/histoplasma/coccidioides +ve
• Bone marrow: active marrow with mild plasmacytosis
• HIV Antibody -ve; p24 Ag –ve
• Ig pattern unremarkable
• Lumbar puncture: normal
He was treated with a course of amphotericin B to a total dose of 2g and was discharged on fluconazole 200mg bd. Clinical and radiological improvement was satisfactory (Fig 2).
Discussion
Inhalation of the spores (arthrocondium) of Coccidioides immitus results in coccidioidomycosis. It is endemic in the southwestern United States -Texas, California, Arizona as well as Mexico and Central and South America. These endemic areas usually have similar climate and soil conditions, which favour the fungal growth. Any disturbance in the soil may lead to an upsurge of the disease, for example, earthquakes, dust stonns as well as archeological digging. The only person-to-person transmission has been indirect, through exposure to contaminated secretions. Patients with coccidioidomycosis do not require isolation if hospitalized, but care must be taken in disposing materials contaminated with secretions.
Approximately 5% -10% of the estimated 100,000 infections occurring annually in the USA will result in residual pulmonary sequelae, usually in the fonD of nodules or peripheral thin-walled cavities. A small proportion (0.5%-1 %) of all infections will result in illnesses related to chronic pulmonary or extrapulmonary (disseminated) infections, the latter commonly involving the skin, the skeletal system and the meninges. Those at higher risk from disseminated disease include male, pregnant women, immunocompromised patients and non-white people.
Diagnosis is by finding spherules containing endospores in tissue specimen although antigen testing is not available. The organisms can be seen in or grown easily from pus and can be detected in other infected material, such as sputum and aspirates of infected areas. Skin test (Coccidioidin) can be done as an intradennal injection of 0.1 ml (1: 100 dilution) and should be read at 48 hours.
It is considered to be positive if the induration is 5 mm or more. In primary infection, 99% will have positive skin test by the second week. However, it is usually negative in chronic progressive pulmonary disease and fulminant tenninal disease. Serological testing may be of prognostic value.
Management issues of the disease are controversial as prospective controlled trials are lacking and the (i)ptimal duration of antifungal treatment is unknown. For most patients, regular reassessment of symptoms and radiological findings to assure resolution without antifungal agents will be sufficient. Amphotericin B and oral azoles remain the treatment of choice when necessary. Secondary prophylaxis with oral azoles should be continued for the immunocompromised as relapse of the infection is common once anti-fungal treatment is stopped. Surgery may be necessary for those with severe haemoptysis, ruptured/enlarging cavitating lesions during chemotherapy, drainage of empyemas, obstructive hydrocephalus and soft tissue/paraspinal abscess.
References
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