Pneumocystis carinii pneumonia in patients with AIDS: evaluation of lavage and staining techniques in diagnosis.

The diagnostic yield of unilateral vs. bilateral bronchoalveolar lavage (BAL) was prospectively evaluated in 65 consecutive patients suspected of having Pneumocystis carinii pneumonia (PCP) complicating acquired immune deficiency syndrome (AIDS). Gram-Weigert (GW), Papanicolaou (PAP), and Gomori's methenamine silver (GMS) stains were used for identification of P. carinii in all cases. Forty-eight patients had PCP that was identified by GW staining of BAL in 47/48 patients followed by PAP/GMS staining of BAL in 44/48 patients and PAP/GMS staining of bronchial washings in 40/48 patients. In patients with bilateral interstitial infiltrates, unilateral lavage was sufficient for diagnosis of PCP when GW stain was utilized. In patients with PCP complicating AIDS, the diagnostic yield of BAL may be increased by use of both GW and GMS stains.

Fatal paratracheal abscess in multiple sclerosis.

Upper airway obstruction resulting from a paratracheal abscess developed insidiously and led to the death of a 43-year-old woman with multiple sclerosis. Repeated nasogastric intubation, required by an exacerbation of bulbar symptoms, may have initiated this unusual infection. Corticotropin and corticosteroid therapy may have impaired immunologic competence and masked fever and other symptoms of inflammation. Hoarseness and inspiratory stridor should not be attributed to laryngeal paresis in patients with multiple sclerosis unless other causes of airway obstruction have been excluded by appropriate diagnostic studies.

Evidence of intragraft interleukin-2-activated killer cells and allospecific cytolytic T lymphocytes in rejecting lung allografts.

In vivo cell-mediated effector mechanisms of allograft destruction were investigated in a canine single-lung transplantation model. This large animal model permits direct longitudinal studies of immune effector cells from the grafts of individual recipients by bronchoalveolar lavage (BAL). Evidence was obtained that two types of cytolytic lymphocytes act as effectors of allograft destruction. Typical allospecific cytolytic T lymphocytes, were detected late in the course of rejection in nonimmunosuppressed recipients and in cyclosporine-treated recipients during the latter stage of drug tapering. The other type of intragraft cytolytic lymphocyte was observed in the early stages of CsA dose tapering and was characterized by ability to lyse xenogeneic targets in a lectin-dependent cytotoxicity assay but inability to kill allogeneic target cells from the lung donor. These cytolytic cells were also detected in the initial stage of lung rejection in non immunosuppressed recipients and in the early period (3 days) of mixed lymphocyte culture. Current interpretation of these data is that these latter effector cells have the characteristics of IL-2-activated killer cells (IAK). Substantial delays in the detection of intragraft donor-specific CTL relative to IAK activity were observed in recipients undergoing CsA dose tapering compared with nonimmunosuppressed recipients. This finding suggests that appropriate CsA treatment may lead to prolonged inhibition of the generation of donor-specific CTL compared with induction of IAK activity. Delayed detection of intragraft donor-specific CTL paralleled the absence of such activity in donor-specific MLC of tolerant lung allografter recipients. The result of CsA therapy may, therefore, be characterized as a state of "partial unresponsiveness," since certain pathways of immune effector activity remain intact after termination of treatment. The differential effect of CsA on various pathways of allograft destruction may have important implications regarding concepts of alloreactivity and T cell-mediated immune responses.

Concanavalin A-dependent cell-mediated cytotoxicity in bronchoalveolar lavage fluid. Correlation with lung allograft rejection in mongrel dogs during cyclosporine dose tapering.

Although cyclosporine (CsA) is widely used as the primary agent for inhibiting the rejection of organ allografts in man, the ideal immunosuppressive regimen for utilizing this drug is still uncertain. To investigate this question, a concanavalin A (con A)-dependent cell-mediated cytotoxicity (CDCMC) assay was used to examine the development of intragraft and peripheral blood cytolytic T lymphocyte activity during CsA dose tapering. These studies were conducted in a canine single-lung transplantation model that facilitates serial examination of intragraft effector cells by bronchoalveolar lavage (BAL). A remarkable correlation of increased intragraft CDCMC and clinical evidence of lung allograft rejection was observed during CsA dose tapering in some recipients. In other recipients CDCMC remained low and evidence of rejection was not observed during drug tapering. In contrast, peripheral blood CDCMC did not correlate well with evidence of rejection. Rejection phenomena observed after termination of CsA therapy were reversed by resumption of CsA treatment but were not reversed by administration of methylprednisolone. Furthermore, the increased level of CDCMC was diminished by reinstitution of CsA therapy at the initial dosage. Following termination of CsA therapy, a prolonged period of unresponsiveness was observed in nearly two-thirds of the recipients, and 60% of these latter dogs had unlimited survival of their lung allografts (median greater than 496 days). Intragraft CDCMC remained low during the periods of unresponsiveness and increased upon onset of rejection. We conclude that measurement of intragraft CDCMC is a useful in vitro method of monitoring lung allograft rejection, and therefore provides a technique for adjusting CsA dosage schedules to achieve maximally effective immunosuppression. The use of this assay for monitoring rejection of other organ grafts requires further investigation.

Bronchial anastomotic healing in canine lung allotransplants treated with cyclosporine.

Bronchial anastomotic healing was evaluated in 22 long-term-surviving canine lung allotransplant recipients treated with cyclosporine as the major immunosuppressive agent. Mean survival in these dogs was over 155 days, and 4 animals survived 1-3 years. Bronchial anastomotic complications were limited to 5 cases of minimal (less than 15%) bronchostenosis. The bronchial anastomoses became somewhat edematous and friable during rejection episodes, but no clinically serious sequelae--such as hemorrhage, peribronchial abscess, or bronchial dehiscence--were observed. Gross and microscopic evaluation of the recipient and donor segments of the anastomoses revealed excellent healing, with only scattered areas of inflammatory cells. The decreased frequency and severity of rejection episodes in animals treated with cyclosporine permits early revascularization of the bronchus to take place and reduces the need for other immunosuppressive agents that may interfere with bronchial healing. Cyclosporine is an effective immunosuppressive agent for canine lung allotransplantation and allows normal bronchial anastomotic healing to occur.

Immunologic, morphologic, and functional evaluation of long-term-surviving beagle lung allograft recipients treated with lethal total-body irradiation, autologous bone marrow, and methotrexate.

Immunologic, morphologic, and functional evaluations were performed in beagle dogs with single lung allografts surviving 3-13 years after transplantation. Immunosuppressive treatment included lethal total-body irradiation, autologous bone marrow reconstitution, and three doses of methotrexate. Three beagle recipients with full DLA-haplotype-matched grafts and five recipients with one-haplotype-mismatched grafts were studied. Evidence of rejection--i.e., infiltrates on chest roentgenograms, hypoperfusion on radionuclide lung scans, and histopathologic changes--were absent in the matched recipients and in three of the five mismatched recipients. Two of the mismatched recipients had decreased perfusion to their allografted lungs, and open-lung biopsy specimens revealed diffuse fibrotic blood vessels with narrowed lumina but no other abnormalities. Decreased fractional blood flow to the lung allograft of the five one-haplotype-mismatched recipients was correlated (r = -0.92) with the level of donor-specific cytolytic lymphocyte activity generated in mixed lymphocyte cultures (MLC). In contrast, the level of proliferative activity in donor-specific MLC did not correlate well with graft function. These findings suggest that the mechanism of tolerance to these lung allografts (with particular regard to vascular integrity) involves attenuation of the response against major histocompatibility complex (MHC) class I alloantigen since the induction of cytolytic T lymphocytes in MLC is directed primarily against these molecules. Though all of the mismatched recipients had the ability to react against MHC class II alloantigens in vitro (as demonstrated by proliferative responses in MLC), in vivo responses to class II gene products may not occur because of the lack of expression of these molecules on long-term surviving grafts.

Cyclosporin A in experimental lung transplantation.

Cyclosporin A (Cy A) has been used in combination with low-dose azathioprine (2 mg/kg/day for 14 days) or other immunosuppressives to treat 13 canine lung allograft recipients. Two of five dogs treated with Cy A and azathioprine survive at 13 and 6 months, respectively, with normal lung function and no evident rejection. The other three dogs in this group survived for over 5 months despite evidence of rejection which was reversed with methylprednisolone (50 mg/kg/day for 3 to 5 days). The addition of prophylactic corticosteroids or their substitution for azathioprine resulted in decreased survival without preventing rejection better. The lung allograft rejection that occurred with Cy A was usually later in onset and more easily reversed by corticosteroids than the lung rejection that occurred with standard immunosuppression. Cy A rejection was also sometimes qualitatively different. Perivascular mononuclear cell cuffs and a proportionally greater decrease in allograft perfusion with respect to ventilation were often more prominent than in rejection with standard immunosuppression. In some instances, decreased allograft perfusion evidenced rejection while the plain chest roentgenogram and ventilation remained normal. Except for infection, which only occurred in animals receiving prophylactic corticosteroids, there was no toxicity from Cy A. These findings indicate that this drug is the safest, most effective immunosuppressive agent yet available for use in lung transplantation.

Reversible pulmonary uptake and hypertrophic pulmonary osteoarthropathic distribution of technetium-99m methylene diphosphonate in a case of Pneumocystis carinii pneumonia.

Diffuse pulmonary deposition of [99mTc]methylene diphosphonate (MDP) as well as abnormalities characteristic of hypertrophic pulmonary osteoarthropathy have been observed in a patient with Pneumocystis carinii pneumonia (PCP). The findings of the bone scan together with those in the corresponding scintigraphy, and roentgenograms of the chest and skeletal structures are presented. Parallel reversal of [67Ga]citrate and [99mTc]MDP pulmonary uptake with specific treatment for and clinical resolution of PCP implies a causal relationship.

Pulmonary manifestations of disseminated cryptococcosis in patients with AIDS.

Forty-eight patients with disseminated cryptococcosis and AIDS were retrospectively studied to define the pulmonary manifestations. Cryptococcus neoformans (CN) was first isolated from a pulmonary site in 12 patients. Disseminated disease was subsequently documented in all these patients. Symptoms and roentgenographic manifestations (normal, nodular/circumscribed infiltrates, pleural effusions, lobar consolidation) were diverse. Interstitial infiltrates predicted the presence of another opportunistic lung infection besides cryptococcosis in five patients (three untreated and two treated patients). Infectious causes other than cryptococcosis were established by culture and clinical course in five of the ten patients who developed chest roentgenographic abnormalities during amphotericin B therapy. Endobronchial abnormalities were identified in four patients at bronchoscopy. Bronchoalveolar lavage (9/9) and pleural fluid (3/3) cultures were sensitive tests for detection of pulmonary involvement with CN.

Utility of bronchoscopic sampling techniques for cryptococcal disease in AIDS.

Although cryptococcal pneumonia is a well recognized complication of the acquired immunodeficiency syndrome, optimal diagnostic approaches remain to be defined. During a 32-month period (October 1984 to June 1987), 11 patients were diagnosed with CP at our institution. The diagnosis was established in all 11 patients from specimens obtained via fiberoptic bronchoscopy (ten) and/or double-lumen catheter lavage (one). Direct stains of sedimented bronchoalveolar lavage were positive for organisms characteristic of Cryptococcus neoformans in nine of 11 patients. Transbronchial biopsies were positive (special histologic stains) in six of eight patients; bronchial washings were positive (direct smear) in seven of ten patients, the bronchial brushings were positive on stain in six of nine patients, and in one patient, a Wang transbronchial needle aspirate was positive on stain. Fungal cultures were positive on the BAL in seven of 11 patients, and on the bronchial washings in four of ten patients; the TBBx culture samples were all negative (zero of three). The serum cryptococcal antigen titer was elevated (median = 1:1024) in all eight patients in which it was assayed. Our data suggest that BAL and bronchial washings have a combined sensitivity on smear equal to that of TBBx and superior to that of TBBx fungal culture. The TBBx does not appear to be necessary in this setting. In addition, an elevated serum cryptococcal antigen titer appears to be an important adjunct in the evaluation of pulmonary infiltrates in AIDS.

Fiberoptic bronchoscopy in the presence of space-occupying intracranial lesions.

The performance of flexible fiberoptic bronchoscopy (FFB) has anecdotally been considered to carry a high risk of neurologic complications in patients with raised intracranial pressure (ICP). There is no evidence in the literature to support this concern. We evaluated this risk by reviewing hospital records of 132 patients who underwent FFB and computer tomography of the central nervous system (CNS-CT) during the same hospitalization. Twenty-nine patients had CT evidence of increased ICP. For the purpose of analysis, patients were divided into two groups: 17 patients had evidence of raised ICP prior to the performance of FFB and had received treatment with an intent to lower the ICP, and 12 patients in whom increased ICP was not suspected at the time of FFB and therefore did not receive any form of pretreatment. There was no evidence of neurologic complications in either group during the first postbronchoscopy week. We conclude that FFB carries a low risk in patients with elevated ICP.

The role of fiberoptic bronchoscopy for diagnosis of pulmonary tuberculosis in patients at risk for AIDS.

In patients with acquired immunodeficiency syndrome (AIDS)-associated pulmonary Mycobacterium tuberculosis (MTB) (group 1), we analyzed whether the addition of transbronchial biopsy (TBB) and bronchial brushings augmented the diagnostic MTB yield over nonbiopsy sampling. Positive acid-fast bacilli (AFB) smears from combined sputum, bronchoalveolar lavage (BAL), and washings were 30 percent compared with 37 percent when brushings and TBB were added (p = NS). The addition of TBB increased culture yield from 96 percent to 100 percent (p = NS). Similar results were seen in patients with pulmonary MTB without human immunodeficiency virus (HIV) risk factors (group 2). Group 1 patients most commonly had a nonspecific inflammation on TBB histopathology and had a lower incidence of granuloma formation than group 2 (p less than 0.05). Our results suggest that more invasive sampling with bronchial brushings and TBB does not contribute to the microscopic, bacteriologic, or histopathologic diagnosis of pulmonary MTB, independent of AIDS risk factors.

Actinomycotic cervical abscess: A complication of transtracheal aspiration.

Transtracheal aspiration is frequently employed to obtain sputum for microbiologic analysis. Infectious complications of this procedure have been reported rarely. We report an actinomycotic anterior cervical abscess traversing the needle track of a transtracheal aspiration in a patient with actinomycotic pneumonia. Organisms most frequently encountered in anterior cervical abscesses complicating transtracheal aspiration have the recognized potential for local invasion of soft tissue from the primary pulmonary lesion.

Usual interstitial pneumonia following Texas A2 influenza infection.

In two patients a documented Texas A2 influenza infection was associated with the development of interstitial pulmonary disease. One patient had an acute fulminating process resulting in respiratory failure and necessitating ventilatory assistance. Open lung biopsy revealed a histologic picture consistent with usual interstitial pneumonia (UIP). The other patient had a subacute course, and the pulmonary histology showed UIP with features of desquamative interstitial pneumonia. The influenza virus may have had an etiologic role in the development of the interstitial lung disease in our two patients.

Influence of bronchial circulation and corticosteroid therapy on bronchial anastomotic healing.

In order to assess the effect of revascularization on the healing of bronchial anastomoses in a canine model, we developed a microsurgical technique that permits the immediate reperfusion of the distal bronchial segment by a direct anastomosis of the bronchial artery to an intercostal artery. This technique was applied to dogs that underwent hilar stripping and bronchial transection and reanastomosis, and it prevented the development of ischemic bronchial damage. In addition, several groups of dogs that had undergone bronchial transection and reanastomosis and, in some cases, reestablishment of bronchial arterial circulation, were treated with 40 mg of prednisone daily for periods of 7 and 21 days. The animals treated with corticosteroids demonstrated a lesser degree of inflammatory damage to the bronchial anastomotic site than similar groups of untreated animals. These findings support the hypothesis that restoration of bronchial arterial blood flow at the time of lung transplantation can reduce anastomotic damage to the distal or donor bronchial component. Our results further suggest that corticosteroid therapy alone does not increase bronchial anastomotic damage, and, in fact, may reduce inflammation at the bronchial anastomotic site.

Effect of donor bronchial length on healing: a canine model to evaluate bronchial anastomotic problems in lung transplantation.

Bronchial anastomotic complications in lung transplantation in man remain a major cause of failure. To study this problem in a canine model, we varied the length of the distal bronchial component in three groups of dogs that underwent hilar stripping, bronchial transection, and reanastomosis, The distal bronchial component was thus analogous to the donor in a transplanted lung. Anastomoses were performed, respectively, at the level of the main carina (long single anastomosis), at the midpoint between the main carina and the bifurcation of the left main-stem bronchus (short single anastomosis), and just distal to the bifurcation of the left main-stem bronchus (lobar anastomosis). Bronchial anastomotic damage and necrosis were evaluated by periodic examination with a fiberoptic bronchoscope and by gross and microscopic examination at sacrifice on the seventh postoperative day. The long single anastomoses demonstrated the most necrosis, and the labor anastomoses showed the least. The short single anastomoses showed an intermediate degree of damage. These findings support the hypothesis that shortening the distal or donor bronchial component reduces anastomotic damage, probably because of better pulmonary-to-bronchial collateral blood supply. This study provides a canine model by which to examine bronchial anastomotic complicatons and demonstrates the feasibility of performing labor anastomoses as a means for decreasing bronchial anastomotic problems in lung transplantation.

Revascularization of ischemic bronchial anastomoses by an intercostal pedicle flap.

Ischemia of the donor bronchus, perfused solely by retrograde collaterals from the pulmonary circulation, is an important factor in the impaired healing of the bronchial anastomosis of transplanted lungs. The healing of two experimental models of bronchial anastomotic ischemia, the bronchial segmental autograft and the postpneumonectomy bronchial autograft, was assessed in dogs. The application of a polytetrafluoroethylene wrap to the bronchial segmental autograft and the application of an intercostal pedicle flap to the postpneumonectomy bronchial autograft, with and without concomitant administration of corticosteroids, were also studied to elucidate factors that affect bronchial anastomotic healing. The bronchial segmental autograft healed normally without stricture, but isolation of this autograft from the mediastinum and lung by the polytetrafluoroethylene wrap resulted in necrosis of the autograft. All dogs that had a postpneumonectomy bronchial autograft died of bronchopleural fistulas due to autograft necrosis. Application of an intercostal pedicle flap to the autograft resulted in healing in all animals. Arteriography and Microfil injection demonstrated revascularization of the postpneumonectomy bronchial autograft by the pedicled intercostal artery. Several conclusions can be drawn: With the lung in situ the bronchial segmental autograft survives, probably as a free composite graft. In contrast, the postpneumonectomy bronchial autograft is an excellent model of bronchial anastomotic ischemia. The intercostal pedicle flap is a reliable method for providing neovascularity and mechanical reinforcement to an ischemic bronchial anastomosis. Its effect on bronchial anastomotic healing was not diminished by administration of corticosteroids. The intercostal pedicle flap may be useful in preventing bronchial anastomotic complications in clinical lung transplantation.

Hypertrophic osteoarthropathy associated with Pneumocystis carinii pneumonia in AIDS.

Hypertrophic osteoarthropathy (HOA) is a systemic disorder primarily affecting the bones, joints, and soft tissues and developing in association with another disease process. Acute pyogenic pulmonary processes (empyema, lung abscess) are occasionally accompanied by transient HOA, but reversible HOA has not previously been reported in the setting of PCP in AIDS.

Single lung transplantation with cyclosporin immunosuppression. Evaluation of canine and human recipients.

Cyclosporin, a potent new immunosuppressive agent, was used (alone or in combination with other drugs) in 28 canine single lung allograft recipients. Mean recipient survival with good allograft function was 155 days with cyclosporin and far exceeded that obtained in previous single lung allograft recipients treated with standard immunosuppression (15 to 22 days). The results of these experiments were as follows: (1) 20% of the recipient animals exhibited no evidence of rejection whatsoever; (2) four of 28 animals survived more than 350 days with good allograft function; (3) 79% of the animals exhibited some evidence of rejection that was easily reversed in 74% of instances with corticosteroids; (4) 10 of 28 animals exhibited good lung allograft function 5 months or more after operation; (5) in cyclosporin-treated lung allograft recipients, rejection was diagnosed by the presence of infiltrate on chest roentgenogram, analysis of the cellular content of bronchoalveolar lavage samples, and decreased perfusion on 99mtechnetium lung scan; (6) complete healing without stenosis of the bronchial anastomosis occurred in 82% of the animals studied. One of two patients treated with cyclosporin after undergoing single lung allografting survived 7 weeks after transplantation and 4 weeks after contralateral pneumonectomy. Episodes of rejection were reversible, and the bronchial anastomosis healed normally. This overall experience indicates that cyclosporin, although not a perfect immunosuppressive agent, increases the likelihood of success with therapeutic single lung transplantation.

Pulmonary non-Hodgkin's lymphoma mimicking infection.

Progressive pulmonary shadows prompted investigations which provided the diagnosis of pulmonary non-Hodgkin's lymphoma in three patients (two with the acquired immunodeficiency syndrome). Rapid progression of radiographic abnormalities seen in these three patients is unusual for pulmonary non-Hodgkin's lymphoma and mimics disease evolution commonly associated with pulmonary infections.